Chemical compounds

ABSTRACT

Compounds of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, 
                         
wherein —N-HET is, for example, (Ic) or (If)
 
                         
wherein R1 is, for example, halogen or a (1–4C)alkyl group which is substituted by one substituent selected from, for example, hydroxy, (1–4C)alkoxy, amino, cyano or azido; Q is selected from, for example, Q1
 
                         
wherein R 2  and R 3  are independently hydrogen or fluoro;
 
T is selected from a range of groups, for example,
 
                         
wherein m is 0, 1 or 2; are useful as antibacterial agents; and processes for their manufacture and pharmaceutical compositions containing them are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB03/00791, filed Feb. 25, 2003, whichclaims priority from U.S. application Ser. No. 60/360,688, filed Feb.28, 2002, the specification of which is incorporated by referenceherein. International Application No. PCT/GB03/00791 was published underPCT Article 21(2) in English.

The present invention relates to antibiotic compounds and in particularto antibiotic compounds containing a substituted oxazolidinone ring.This invention further relates to processes for their preparation, tointermediates useful in their preparation, to their use as therapeuticagents and to pharmaceutical compositions containing them.

The international microbiological community continues to express seriousconcern that the evolution of antibiotic resistance could result instrains against which currently available antibacterial agents will beineffective. In general, bacterial pathogens may be classified as eitherGram-positive or Gram-negative pathogens. Antibiotic compounds witheffective activity against both Gram-positive and Gram-negativepathogens are generally regarded as having a broad spectrum of activity.The compounds of the present invention are regarded as principallyeffective against Gram-positive pathogens.

Gram-positive pathogens, for example Staphylococci, Enterococci, andStreptococci are particularly important because of the development ofresistant strains which are both difficult to treat and difficult toeradicate from the hospital environment once established. Examples ofsuch strains are methicillin resistant staphylococcus (MRSA),methicillin resistant coagulase negative staphylococci (MRCNS),penicillin resistant Streptococcus pneumoniae and multiply resistantEnterococcus faecium.

The major clinically effective antibiotic for treatment of suchresistant Gram-positive pathogens is vancomycin. Vancomycin is aglycopeptide and is associated with various toxicities includingnephrotoxicity. Furthermore, and most importantly, antibacterialresistance to vancomycin and other glycopeptides is also appearing. Thisresistance is increasing at a steady rate rendering these agents lessand less effective in the treatment of Gram-positive pathogens. There isalso now increasing resistance appearing towards agents such asβ-lactams, quinolones and macrolides used for the treatment of upperrespiratory tract infections, also caused by certain Gram negativestrains including H. influenzae and M. catarrhalis.

Certain antibacterial compounds containing an oxazolidinone ring havebeen described in the art (for example, Walter A. Gregory et al in J.Med. Chem. 1990, 33, 2569–2578 and Chung-Ho Park et al in J. Med. Chem.1992, 35, 1156–1165). Such antibacterial oxazolidinone compounds with a5-acetamidomethyl side-chain may be subject to mammalian peptidasemetabolism. Furthermore, bacterial resistance to known antibacterialagents may develop, for example, by (i) the evolution of active bindingsites in the bacteria rendering a previously active pharmacophore lesseffective or redundant, (ii) the evolution of means to chemicallydeactivate a given pharmacophore and/or (iii) the development and/orup-regulation of efflux mechanisms. Therefore, there remains an ongoingneed to find new antibacterial agents with a favourable pharmacologicalprofile, in particular for compounds containing new pharmacophores.

Additionally, certain antibacterial compounds containing anoxazolidinone ring have activity against the enzyme mono-amine oxidase(MAO), for instance compounds with amidomethyl or hydroxymethyl sidechains at C-5 of the oxazolidinone ring. This may potentially lead toundesirable properties such as elevation in blood pressure whenadministered to a patient, or potentially cause drug-drug interactions.Therefore, there remains an ongoing need to find new antibacterialagents of the oxazolidinone class with a more favourable profile againstMAO.

We have discovered a new class of antibiotic compounds containing anoxazolidinone ring substituted by a 5-azolylmethyl moiety in which theazole group is linked via a nitrogen atom and is itself furthersubstituted. These compounds have useful activity against Gram-positivepathogens including MRSA and MRCNS and, in particular, against variousstrains exhibiting resistance to vancomycin and against E. faeciumstrains resistant to both aminoglycosides and clinically used β-lactams,but also to certain fastidious Gram negative strains such as H.influenzae, M. catarrhalis and chlamydial strains. The compounds of theinvention also show a favourable, decreased, MAO potency compared withother oxazolidinone analogues from the prior art.

Accordingly in a first aspect, the present invention provides a compoundof the formula (I), or a pharmaceutically-acceptable salt, or anin-vivo-hydrolysable ester thereof,

wherein —N-HET is selected from the structures (Ia) to (If) below:

wherein u and v are independently 0 or 1;

-   R1 is selected from a substituent from the group-   (R1a) wherein R1 is halogen, hydroxy, (1–4C)alkoxy,    (2–4C)alkenyloxy, (2–4C)alkenyl, (2–4C)alkynyl (optionally    substituted on the terminal carbon by CH₂═CH—, di(1–4C)alkylamino,    AR2, AR2a or AR2b, wherein AR2, AR2a and AR2b are defined    hereinbelow), (3–6C)cycloalkyl, (3–6C)cycloalkenyl, amino,    (1–4C)alkylamino, di-(1–4C)alkylamino, (2–4C)alkenylamino,    (1–4C)alkyl-S(O)q- (wherein q is 0, 1 or 2),    (1–4C)alkylcarbonylamino;-   or R1 is selected from the group-   (R1b) wherein R1 is a (1–4C)alkyl group which is substituted by one    substituent selected from hydroxy, halo, (1–4C)alkoxy, amino,    (1–4C)alkylamino, di(1–4C)alkylamino, cyano, azido,    (2–4C)alkenyloxy, (1–4C)alkyl-S(O)q- (wherein q is 0, 1 or 2),    AR1-S(O)q- (wherein q is 0, 1 or 2 and AR1 is defined hereinbelow),    AR2-S(O)q- (wherein q is 0, 1 or 2), AR2a-S(O)q- (wherein q is 0, 1    or 2), benzyl-S(O)q- (wherein q is 0, 1 or 2), (3–6C)cycloalkyl,    (3–6C)cycloalkenyl, (1–4C)alkyl-OCO—NH—, (1–4C)alkyl-NHCO—O—,    (1–4C)alkylaminocarbonyl, di(1–4C)alkylaminocarbonyl, H₂NC(═NH)S—;-   or R1 is selected from a group of formula (R1c1):-   (R1c1) a fully saturated 4-membered monocyclic ring containing 1 or    2 heteroatoms independently selected from O, N and S (optionally    oxidised), and linked via a ring nitrogen or carbon atom; or    or R1 is selected from the group-   (R1d) cyano, nitro, azido, formyl, (1–4C)alkylcarbonyl,    (1–4C)alkoxycarbonyl, H₂NC(O)—, ((1–4C)alkyl)NHC(O)—;    and wherein at each occurrence of an R1 substituent containing an    alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety in (R1a),    (R1b) or (R1c1) each such moiety is optionally further substituted    on an available carbon atom with one, two, three or more    substituents independently selected from F, Cl Br, OH and CN;-   Q is selected from Q1 to Q6:

wherein R² and R³ independently selected from H, F, Cl, CF₃, OMe, SMe,Me and Et;

-   wherein B₁ is O or S;-   wherein T is selected from the groups in (TA) to (TE) below (wherein    AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are    defined hereinbelow);-   (TA) T is selected from the following groups:-   (TAa) AR1 or AR3; or-   (TAb) a group of formula (TAb1) to (TAb6):

wherein:

-   R⁶ is selected (independently where appropriate) from hydrogen,    (1–4C)alkyl, (1–4C)alkoxycarbonyl, (1–4C)alkanoyl, carbamoyl and    cyano;-   R⁴ and R⁵ are independently selected from hydrogen, halo,    trifluoromethyl, cyano, azido, nitro, (1–4C)alkoxy,    (1–4C)alkylS(O)_(q)— (q is 0, 1 or 2), (1–4C)alkanoyl,    (1–4C)alkoxycarbonyl, benzyloxy-(1–4C)alkyl, (2–4C)alkanoylamino,    hydroxyimino, (1–4C)alkoxyimino, —CONRcRv and —NRcRv wherein any    (1–4C)alkyl group contained in the preceding values for R⁴ and R⁵ is    optionally substituted by up to three substituents independently    selected from hydroxy or azido (neither of such substituents on C1    of an alkoxy group, and excluding geminal disubstitution), oxo,    trifluoromethyl, cyano, nitro, (1–4C)alkoxy, (2–4C)alkanoyloxy,    hydroxyimino, (1–4C)alkoxyimino, (1–4C)alkylS(O)_(q)— (q is 0, 1 or    2), (1–4C)alkylSO₂—NRv-, (1–4C)alkoxycarbonyl, —CONRcRv, and —NRcRv    (not on C1 of an alkoxy group, and excluding geminal    disubstitution); wherein Rv is hydrogen or (1–4C)alkyl and Rc is as    hereinafter defined;-   R⁴ and R⁵ may further be independently selected from (1–4C)alkyl    {optionally substituted by up to three substituents independently    selected from hydroxy or azido (both of such substituents excluded    from geminal disubstitution), oxo, trifluoromethyl, cyano, nitro,    (1–4C)alkoxy, (2–4C)alkanoyloxy, hydroxyimino, (1–4C)alkoxyimino,    (1–4C)alkylS(O)_(q)— (q is 0, 1 or 2), (1–4C)alkylSO₂—NRv-,    (1–4C)alkoxycarbonyl, —CONRcRv, and —NRcRv (excluding geminal    disubstitution); wherein Rv is hydrogen or (1–4C)alkyl}; Rc is as    hereinafter defined;    and wherein-   any (1–4C)alkyl group contained in the immediately preceding    optional substituents (when R⁴ and R⁵ are independently (1–4C)alkyl)    is itself optionally substituted by up to three substituents    independently selected from hydroxy (not on C1 of an alkoxy group,    and excluding geminal disubstitution), oxo, trifluoromethyl, cyano,    nitro, (1–4C)alkoxy, (2–4C)alkanoyloxy, hydroxyimino,    (1–4C)alkoxyimino, (1–4C)alkylS(O)_(q)— (q is 0, 1 or 2),    (1–4C)alkylSO₂—NRv-, (1–4C)alkoxycarbonyl, —CONRcRv, and —NRcRv (not    on C1 of an alkoxy group, and excluding geminal disubstitution);    wherein Rv is hydrogen or (1–4C)alkyl and Rc is as hereinafter    defined;-   or R⁴ is selected from one of the groups in (TAba) to (TAbc) below,    or (where appropriate) one of R⁴ and R⁵ is selected from the above    list of R⁴ and R⁵ values, and the other is selected from one of the    groups in (TAba) to (TAbc) below:-   (TAba) a group of the formula (TAba1)

wherein Z⁰ is hydrogen or (1–4C)alkyl;

-   X⁰ and Y⁰ are independently selected from hydrogen, (1–4C)alkyl,    (1–4C)alkoxycarbonyl, halo, cyano, nitro, (1–4C)alkylS(O)_(q)— (q is    0, 1 or 2), RvRwNSO₂—, trifluoromethyl, pentafluoroethyl,    (1–4C)alkanoyl and —CONRvRw [wherein Rv is hydrogen or (1–4C)alkyl;-   Rw is hydrogen or (1–4C)alkyl]; or-   one of X⁰ and Y⁰ is selected from the above list of X⁰ and Y⁰    values, and the other is selected from phenyl, phenylcarbonyl,    —S(O)_(q)-phenyl (q is 0, 1 or 2), N-(phenyl)carbamoyl,    phenylaminosulfonyl, AR2, (AR2)-CO—, (AR2)-S(O)_(q)— (q is 0, 1 or    2), N-(AR2)carbamoyl and (AR2)aminosulfonyl; wherein any phenyl    group in (TAba) may be optionally substituted by up to three    substituents independently selected from (1–4C)alkyl, cyano,    trifluoromethyl, nitro, halo and (1–4C)alkylsulfonyl;-   (TAbb) an acetylene of the formula -≡—H or -≡-(1–4C)alkyl;-   (TAbc) —X¹—Y¹-AR2, —X¹—Y¹-AR2a, —X¹—Y¹-AR2b, —X¹—Y¹-AR3, —X¹—Y¹-AR3a    or —X¹—Y¹-AR3b;    wherein X¹ is a direct bond or —CH(OH)— and-   Y¹ is —(CH₂)_(m)—, —(CH₂)_(n)—NH—(CH₂)_(m)—, —CO—(CH₂)_(m)—,    —CONH—(CH₂)_(m)—, —C(═S)NH—(CH₂)_(m)— or —C(═O)O—(CH₂)_(m)—;-   or wherein X¹ is —(CH₂)_(n)— or —CH(Me)-(CH₂)_(m)— and-   Y¹ is —(CH₂)_(m)—NH—(CH₂)_(m)—, —CO—(CH₂)_(m)—, —CONH—(CH₂)_(m)—,    —C(═S)NH—(CH₂)_(m)—, —C(═O)O—(CH₂)_(m)— or —S(O)_(q)—(CH₂)_(m)—;-   or wherein X¹ is —CH₂O—, —CH₂NH— or —CH₂N((1–4C)alkyl)- and-   Y¹ is —CO—(CH₂)_(m)—, —CONH—(CH₂)_(m)— or —C(═S)NH—(CH₂)_(m)—; and    additionally Y¹ is —SO₂— when X¹ is —CH₂NH— or —CH₂N((1–4C)alkyl)-,    and Y¹ is —(CH₂)_(m)— when X¹ is —CH₂O— or —CH₂N((1–4C)alkyl)-;    wherein n is 1, 2 or 3; m is 0, 1, 2 or 3 and q is 0, 1 or 2; and    when Y¹ is —(CH₂)_(m)—NH—(CH₂)_(m)— each m is independently selected    from 0, 1, 2 or 3; or-   (TB) T is selected from halo, formyl or —NRv¹Rw¹; or is selected    from the following groups:-   (TBa) R¹⁰CO—, R¹⁰S(O)_(q)— (q is 0, 1 or 2) or R¹⁰CS—    wherein R¹⁰ is selected from the following groups:-   (TBaa) CY1 or CY2;-   (TBab) (1–4C)alkoxycarbonyl, trifluoromethyl, —NRvRw, ethenyl,    2-(1–4C)alkylethenyl, 2-cyanoethenyl,    2-cyano-2-((1–4C)alkyl)ethenyl, 2-nitroethenyl,    2-nitro-2-((1–4C)alkyl)ethenyl, 2-((1–4C)alkylaminocarbonyl)ethenyl,    2-((1–4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl or 2-(AR2)ethenyl;    or-   (TBac) (1–4C)alkyl {optionally substituted by one or more groups    each independently selected from hydroxy, (1–4C)alkoxy,    (1–4C)alkanoyl, cyano, halo, trifluoromethyl, (1–4C)alkoxycarbonyl,    —NRvRw, (1–6C)alkanoylamino, (1–4C)alkoxycarbonylamino,    N-(1–4C)alkyl-N-(1–6C)alkanoylamino, (1–4C)alkylS(O)_(q)— (q is 0, 1    or 2), CY1, CY2, AR1, (1–4C)alkylS(O)_(p)NH— or    (1–4C)alkylS(O)_(p)-((1–4C)alkyl)N— (p is 1 or 2)};    wherein Rv is hydrogen or (1–4C)alkyl; Rw is hydrogen or    (1–4C)alkyl; Rv¹ is hydrogen, (1–4C)alkyl or (3–8C)cycloalkyl; Rw¹    is hydrogen, (1–4C)alkyl, (3–8C)cycloalkyl, formyl, (1–4C)alkyl-CO—    or (1–4C)alkylS(O)_(q)— (q is 1 or 2); or-   (TC) T is selected from a group of formula (TC1) to (TC4):

wherein in (TC1): >A₃-B₃— is >C(Rq)-CH(Rr)- or >N—CH₂— and G is —O—,—S—, —SO—, —SO₂— or >N(Rc);wherein in (TC2): m1 is 0, 1 or 2; >A₃-B₃— is >C═C(Rr)-or >C(Rq)-CH(Rr)- or >N—CH₂— and G is —O—, —S—, —SO—, —SO₂— or >N(Rc);wherein in (TC3): m1 is 0, 1 or 2; >A₃-B₃— is >C(Rq)-CH(Rr)- (other thanwhen Rq and Rr are both together hydrogen) or >N—CH₂— and G is —O—, —S—,—SO—, —SO₂— or >N(Rc);wherein in (TC4): n1 is 1 or 2; o1 is 1 or 2 and n1+o1=2 or 3; >A₃-B₃—is >C═C(Rr)- or >C(Rq)-CH(Rr)- or >N—CH₂— and G is —O—, —S—, —SO—, —SO₂—or >N(Rc); Rp is hydrogen, (1–4C)alkyl (other than when suchsubstitution is defined by >A₃-B₃—), hydroxy, (1–4C)alkoxy or(1–4C)alkanoyloxy;wherein in (TC1), (TC2) and (TC4); m1, n1 and o1 are as definedhereinbefore in (TC): >A₃-B₃— is >N—CH₂— and G is>(R¹¹)(R¹²), >C═O, >C—OH, >C-(1–4C)alkoxy, >C═N—OH, >C═N-(1–4C)alkoxy, >C═N—NH-(1–4C)alkyl,>C═N—N((1–4C)alkyl)₂ (the last two (1–4C)alkyl groups above in G beingoptionally substituted by hydroxy) or >C═N—N—CO-(1–4C)alkoxy;wherein >represents two single bonds;

-   Rq is hydrogen, hydroxy, halo, (1–4C)alkyl or (1–4C)alkanoyloxy;-   Rr is (independently where appropriate) hydrogen or (1–4C)alkyl;-   R¹¹ is hydrogen, (1–4C)alkyl, fluoro(1–4C)alkyl,    (1–4C)alkyl-thio-(1–4C)alkyl or hydroxy-(1–4C)alkyl and R¹² is    —[C(Rr)(Rr)]_(m2)-N(Rr)(Rc) wherein m2 is 0, 1 or 2;    and, other than the ring substitution defined by G, >A₃-B₃— and Rp,    each ring system may be optionally further substituted on a carbon    atom not adjacent to the link at >A₃- by up to two substituents    independently selected from (1–4C)alkyl, fluoro(1–4C)alkyl    (including trifluoromethyl), (1–4C)alkyl-thio-(1–4C)alkyl,    hydroxy-(1–4C)alkyl, amino, amino-(1–4C)alkyl, (1–4C)alkanoylamino,    (1–4C)alkanoylamino-(1–4C)alkyl, carboxy, (1–4C)alkoxycarbonyl,    ARc-oxymethyl, ARc-thiomethyl, oxo (═O) (other than when G is >N-Rc    and Rc is group (Rc2) defined hereinbefore) or independently    selected from Rc (if such substituents are not already defined    herein in (TC)); and also hydroxy or halo (the last two optional    substituents only when G is —O— or —S—);    wherein ARc is selected from AR1, AR2, AR2a, AR2b, CY1 and CY2    defined hereinafter and Rc is selected from groups (Rc1) to (Rc5)    defined hereinafter; or-   (TD) T is selected from the following groups:-   (TDa) a bicyclic spiro-ring system of formula (TDa1) to (TDa9):

wherein;

-   (i) the A₄ linking group is a nitrogen atom or an sp³ or sp² carbon    atom (with the double bond, where appropriate, orientated in either    direction); and-   (ii) one of the ring carbon atoms at positions marked * and ** is    replaced by one of the following groups    —NRc-, >CH—NHRc, >CH—NRc-(1–4C)alkyl, >CH—CH₂—NHRc,    >CH—CH₂—NRc-(1–4C)alkyl [wherein a central —CH₂— chain link is    optionally mono- or di-substituted by (1–4C)alkyl]; with the    provisos that positions marked * are not replaced by —NH— in the    ring containing the A₄ link when A₄ is a nitrogen atom or an sp²    carbon atom, and that positions marked * are not replaced by —NH— in    the three membered ring in (TDa1), (TDa4) and (TDa5); and-   (iii) the ring system is optionally (further) substituted on an    available ring carbon atom by up to two substituents independently    selected from (1–4C)alkyl, fluoro(1–4C)alkyl (including    trifluoromethyl), (1–4C)alkyl-thio-(1–4C)alkyl, hydroxy-(1–4C)alkyl,    amino, amino-(1–4C)alkyl, (1–4C)alkanoylamino,    (1–4C)alkanoylamino-(1–4C)alkyl, carboxy, (1–4C)alkoxycarbonyl,    AR2-oxymethyl, AR2-thiomethyl, oxo (═O) (other than when the ring    contains an >N-Rc and Rc is group (Rc2)) and also hydroxy or halo;    and Rc is selected from groups (Rc1) to (Rc5) defined hereinafter;    or-   (TDb) a 7-, 8- or 9-membered bicyclic ring system containing a    bridge of 0, 1 or 2 carbon atoms of formula (TDb1) to (TDb14):

wherein;

-   (i) the ring system contains 0, 1 or 2 ring nitrogen atoms (and    optionally a further O or S ring heteroatom), and when present the    ring nitrogen, O or S heteroatom/s are at any position other than as    part of the 3-membered ring in (TDb1);-   (ii) the ring system is linked via a ring nitrogen atom or a ring    sp³ or sp² carbon atom (with the double bond, where appropriate,    orientated in either direction) from any position in either ring    [other than from a bridgehead position or from an sp² carbon atom in    the 4-membered ring in (TDb2), (TDb6) and (TDb11)];-   (iii) one of the ring carbon atoms at a position not adjacent to the    linking position, is replaced (other than when the ring contains an    O or S heteroatom) by one of the following groups —NRc- [not at a    bridgehead position], >C(H)—NHRc, >C(H)—NRc-(1–4C)alkyl,    >C(H)—CH₂—NHRc, >C(H)—CH₂—NRc-(1–4C)alkyl [wherein the hydrogen atom    shown in brackets is not present when the replacement is made at a    bridgehead position and wherein a central —CH₂— chain link is    optionally mono- or di-substituted by (1–4C)alkyl]; with the proviso    that when the ring system is linked via a ring nitrogen atom or an    sp² carbon atom any replacement of a ring carbon atom by —NRc-, O or    S is at least two carbon atoms away from the linking position; and-   (iv) the ring system is optionally (further) substituted on an    available ring carbon atom as for the bicyclic spiro-ring systems    described in (TDa); and Rc is selected from groups (Rc1) to (Rc5)    defined hereinafter; or-   (TE) T is selected from the following groups (TE1) to (TE3):

wherein m is 0, 1 or 2; and ( )n₁, ( )o₁, ( )n_(1′), ( )o_(1′), ( )p₁and ( )p_(1′) represent chains of carbon atoms (optionally substitutedas defined for AR1 hereinafter) of length n₁, o₁, n_(1′), o_(1′), p₁ andp_(1′) respectively, and are independently 0–2, with the proviso that in(TE1) and (TE2) the sum of n₁, o₁, n_(1′) and o_(1′) does not exceed 8(giving a maximum ring size of 14 in (TE1) and 11 in (TE2)), and in(TE3) the sum of n₁, o₁, n_(1′), o_(1′), p₁ and p_(1′) does not exceed 6(giving a maximum ring size of 12);wherein Rc is selected from groups (Rc1) to (Rc5):

-   (Rc1) (1–6C)alkyl {optionally substituted by one or more    (1–4C)alkanoyl groups (including geminal disubstitution) and/or    optionally monosubstituted by cyano, (1–4C)alkoxy, trifluoromethyl,    (1–4C)alkoxycarbonyl, phenyl (optionally substituted as for AR1    defined hereinafter), (1–4C)alkylS(O)_(q)— (q is 0, 1 or 2); or, on    any but the first carbon atom of the (1–6C)alkyl chain, optionally    substituted by one or more groups (including geminal disubstitution)    each independently selected from hydroxy and fluoro, and/or    optionally monosubstituted by oxo, —NRvRw [wherein Rv is hydrogen or    (1–4C)alkyl; Rw is hydrogen or (1–4C)alkyl], (1–6C)alkanoylamino,    (1–4C)alkoxycarbonylamino, N-(1–4C)alkyl-N-(1–6C)alkanoylamino,    (1–4C)alkylS(O)_(p)NH— or (1–4C)alkylS(O)_(p)—((1–4C)alkyl)N— (p is    1 or 2)};-   (Rc2) formyl, R¹³CO—, R¹³SO₂— or R¹³CS—    wherein R¹³ is selected from (Rc2a) to (Rc2e):-   (Rc2a) AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;    (Rc2b) (1–4C)alkoxycarbonyl, trifluoromethyl, —NRvRw [wherein Rv is    hydrogen or (1–4C)alkyl; Rw is hydrogen or (1–4C)alkyl], ethenyl,    2-(1–4C)alkylethenyl, 2-cyanoethenyl,    2-cyano-2-((1–4C)alkyl)ethenyl, 2-nitroethenyl,    2-nitro-2-((1–4C)alkyl)ethenyl, 2-((1–4C)alkylaminocarbonyl)ethenyl,    2-((1–4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl,    2-(AR2a)ethenyl;-   (Rc2c) (1–10C)alkyl    {optionally substituted by one or more groups (including geminal    disubstitution) each independently selected from hydroxy,    (1–10C)alkoxy, (1–4C)alkoxy-(1–4C)alkoxy,    (1–4C)alkoxy-(1–4C)alkoxy-(1–4C)alkoxy, (1–4C)alkanoyl, carboxy,    phosphoryl [—O—P(O)(OH)₂, and mono- and di-(1–4C)alkoxy derivatives    thereof], phosphiryl [—O—P(OH)₂ and mono- and di-(1–4C)alkoxy    derivatives thereof], and amino; and/or optionally substituted by    one group selected from phosphonate [phosphono, —P(O)(OH)₂, and    mono- and di-(1–4C)alkoxy derivatives thereof], phosphinate [—P(OH)₂    and mono- and di-(1–4C)alkoxy derivatives thereof], cyano, halo,    trifluoromethyl, (1–4C)alkoxycarbonyl,    (1–4C)alkoxy-(1–4C)alkoxycarbonyl,    (1–4C)alkoxy-(1–4C)alkoxy-(1–4C)alkoxycarbonyl, (1–4C)alkylamino,    di((1–4C)alkyl)amino, (1–6C)alkanoylamino,    (1–4C)alkoxycarbonylamino, N-(1–4C)alkyl-N-(1–6C)alkanoylamino,    (1–4C)alkylaminocarbonyl, di((1–4C)alkyl)aminocarbonyl,    (1–4C)alkylS(O)_(p)NH—, (1–4C)alkylS(O)_(p)-((1–4C)alkyl)N—,    fluoro(1–4C)alkylS(O)_(p)NH—,    fluoro(1–4C)alkylS(O)_(p)((1–4C)alkyl)N—, (1–4C)alkylS(O)_(q)— [the    (1–4C)alkyl group of (1–4C)alkylS(O)_(q)— being optionally    substituted by one substituent selected from hydroxy, (1–4C)alkoxy,    (1–4C)alkanoyl, phosphoryl [—O—P(O)(OH)₂, and mono- and    di-(1–4C)alkoxy derivatives thereof], phosphiryl [—O—P(OH)₂ and    mono- and di-(1–4C)alkoxy derivatives thereof], amino, cyano, halo,    trifluoromethyl, (1–4C)alkoxycarbonyl,    (1–4C)alkoxy-(1–4C)alkoxycarbonyl,    (1–4C)alkoxy-(1–4C)alkoxy-(1–4C)alkoxycarbonyl, carboxy,    (1–4C)alkylamino, di((1–4C)alkyl)amino, (1–6C)alkanoylamino,    (1–4C)alkoxycarbonylamino, N-(1–4C)alkyl-N-(1–6C)alkanoylamino,    (1–4C)alkylaminocarbonyl, di((1–4C)alkyl)aminocarbonyl,    (1–4C)alkylS(O)_(p)NH—, (1–4C)alkylS(O)_(p)—((1–4C)alkyl)N—,    (1–4C)alkylS(O)_(q)—, AR1-S(O)_(q)—, AR2-S(O)_(q)—, AR3-S(O)_(q)—    and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3    containing groups], CY1, CY2, AR1, AR2, AR3, AR1-O—, AR2-O—, AR3-O—,    AR1-S(O)_(q)—, AR2-S(O)_(q)—, AR3—S(O)_(q)—, AR1-NH—, AR2-NH—,    AR3-NH— (p is 1 or 2 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a    and AR3b versions of AR2 and AR3 containing groups};-   (Rc2d) R¹⁴C(O)O(1–6C)alkyl wherein R¹⁴ is AR1, AR2, (1–4C)alkylamino    (the (1–4C)alkyl group being optionally substituted by    (1–4C)alkoxycarbonyl or by carboxy), benzyloxy-(1–4C)alkyl or    (1–10C)alkyl {optionally substituted as defined for (Rc2c)};-   (Rc2e) R¹⁵O— wherein R¹⁵ is benzyl, (1–6C)alkyl {optionally    substituted as defined for (Rc2c)}, CY1, CY2 or AR2b;-   (Rc3) hydrogen, cyano, 2-cyanoethenyl,    2-cyano-2-((1–4C)alkyl)ethenyl, 2-((1–4C)alkylaminocarbonyl)ethenyl,    2-((1–4C)alkoxycarbonyl)ethenyl, 2-nitroethenyl,    2-nitro-2-((1–4C)alkyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or    of the formula (Rc3a)

wherein X⁰⁰ is —OR¹⁷, —SR¹⁷, —NHR¹⁷ and —N(R¹⁷)₂;wherein R¹⁷ is hydrogen (when X⁰⁰ is —NHR¹⁷ and —N(R¹⁷)₂), and R¹⁷ is(1–4C)alkyl, phenyl or AR2 (when X⁰⁰ is —OR¹⁷, —SR¹⁷ and —NHR¹⁷); andR¹⁶ is cyano, nitro, (1–4C)alkylsulfonyl, (4–7C)cycloalkylsulfonyl,phenylsulfonyl, (1–4C)alkanoyl and (1–4C)alkoxycarbonyl;

-   (Rc4) trityl, AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b;-   (Rc5) RdOC(Re)═CH(C═O)—, RfC(═O)C(═O)—, RgN═C(Rh)C(═O)— or    RiNHC(Rj)═CHC(═O)— wherein Rd is (1–6C)alkyl; Re is hydrogen or    (1–6C)alkyl, or Rd and Re together form a (3–4C)alkylene chain; Rf    is hydrogen, (1–6C)alkyl, hydroxy(1–6C)alkyl,    (1–6C)alkoxy(1–6C)alkyl, —NRvRw [wherein Rv is hydrogen or    (1–4C)alkyl; Rw is hydrogen or (1–4C)alkyl], (1–6C)alkoxy,    (1–6C)alkoxy(1–6C)alkoxy, hydroxy(2–6C)alkoxy,    (1–4C)alkylamino(2–6C)alkoxy, di-(1–4C)alkylamino(2–6C)alkoxy; Rg is    (1–6C)alkyl, hydroxy or (1–6C)alkoxy; Rh is hydrogen or (1–6C)alkyl;    Ri is hydrogen, (1–6C)alkyl, AR1, AR2, AR2a, AR2b and Rj is hydrogen    or (1–6C)alkyl;    wherein-   AR1 is an optionally substituted phenyl or optionally substituted    naphthyl;-   AR2 is an optionally substituted 5- or 6-membered, fully unsaturated    (i.e with the maximum degree of unsaturation) monocyclic heteroaryl    ring containing up to four heteroatoms independently selected from    O, N and S (but not containing any —O—O, O—S or S—S bonds), and    linked via a ring carbon atom, or a ring nitrogen atom if the ring    is not thereby quaternised;-   AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systems    retaining some, but not the full, degree of unsaturation), linked    via a ring carbon atom or linked via a ring nitrogen atom if the    ring is not thereby quaternised;-   AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having    no unsaturation), linked via a ring carbon atom or linked via a ring    nitrogen atom;-   AR3 is an optionally substituted 8-, 9- or 10-membered, fully    unsaturated (i.e with the maximum degree of unsaturation) bicyclic    heteroaryl ring containing up to four heteroatoms independently    selected from O, N and S (but not containing any O—O, O—S or S—S    bonds), and linked via a ring carbon atom in either of the rings    comprising the bicyclic system;-   AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systems    retaining some, but not the full, degree of unsaturation), linked    via a ring carbon atom, or linked via a ring nitrogen atom if the    ring is not thereby quaternised, in either of the rings comprising    the bicyclic system;-   AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having    no unsaturation), linked via a ring carbon atom, or linked via a    ring nitrogen atom, in either of the rings comprising the bicyclic    system;-   AR4 is an optionally substituted 13- or 14-membered, fully    unsaturated (i.e with the maximum degree of unsaturation) tricyclic    heteroaryl ring containing up to four heteroatoms independently    selected from O, N and S (but not containing any O—O, O—S or S—S    bonds), and linked via a ring carbon atom in any of the rings    comprising the tricyclic system;-   AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systems    retaining some, but not the full, degree of unsaturation), linked    via a ring carbon atom, or linked via a ring nitrogen atom if the    ring is not thereby quaternised, in any of the rings comprising the    tricyclic system;-   CY1 is an optionally substituted cyclobutyl, cyclopentyl or    cyclohexyl ring;-   CY2 is an optionally substituted cyclopentenyl or cyclohexenyl ring;    wherein; optional substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a,    AR3b, AR4, AR4a, CY1 and CY2 are (on an available carbon atom) up to    three substituents independently selected from (1–4C)alkyl    {optionally substituted by substituents selected independently from    hydroxy, trifluoromethyl, (1–4C)alkyl S(O)_(q)— (q is 0, 1 or 2),    (1–4C)alkoxy, (1–4C)alkoxycarbonyl, cyano, nitro,    (1–4C)alkanoylamino, —CONRvRw or —NRvRw}, trifluoromethyl, hydroxy,    halo, nitro, cyano, thiol, (1–4C)alkoxy, (1–4C)alkanoyloxy,    dimethylaminomethyleneaminocarbonyl,    di(N-(1–4C)alkyl)aminomethylimino, carboxy, (1–4C)alkoxycarbonyl,    (1–4C)alkanoyl, (1–4C)alkylSO₂amino, (2–4C)alkenyl {optionally    substituted by carboxy or (1–4C)alkoxycarbonyl}, (2–4C)alkynyl,    (1–4C)alkanoylamino, oxo (═O), thioxo (═S), (1–4C)alkanoylamino {the    (1–4C)alkanoyl group being optionally substituted by hydroxy},    (1–4C)alkyl S(O)_(q)— (q is 0, 1 or 2) {the (1–4C)alkyl group being    optionally substituted by one or more groups independently selected    from cyano, hydroxy and (1–4C)alkoxy}, —CONRvRw or —NRvRw [wherein    Rv is hydrogen or (1–4C)alkyl; Rw is hydrogen or (1–4C)alkyl];    and further optional substituents on AR1, AR2, AR2a, AR2b, AR3,    AR3a, AR3b, AR4, AR4a, CY1 and CY2 (on an available carbon atom),    and also on alkyl groups (unless indicated otherwise) are up to    three substituents independently selected from trifluoromethoxy,    benzoylamino, benzoyl, phenyl {optionally substituted by up to three    substituents independently selected from halo, (1–4C)alkoxy or    cyano}, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine,    pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole,    thiophene, hydroxyimino(1–4C)alkyl, (1–4C)alkoxyimino(1–4C)alkyl,    halo-(1–4C)alkyl, (1–4C)alkanesulfonamido, —SO₂NRvRw [wherein Rv is    hydrogen or (1–4C)alkyl; Rw is hydrogen or (1–4C)alkyl]; and    optional substituents on AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and    AR4a are (on an available nitrogen atom, where such substitution    does not result in quaternization) (1–4C)alkyl, (1–4C)alkanoyl    {wherein the (1–4C)alkyl and (1–4C)alkanoyl groups are optionally    substituted by (preferably one) substituents independently selected    from cyano, hydroxy, nitro, trifluoromethyl, (1–4C)alkyl S(O)_(q)—    (q is 0, 1 or 2), (1–4C)alkoxy, (1–4C)alkoxycarbonyl,    (1–4C)alkanoylamino, —CONRvRw or —NRvRw [wherein Rv is hydrogen or    (1–4C)alkyl; Rw is hydrogen or (1–4C)alkyl]}, (2–4C)alkenyl,    (2–4C)alkynyl, (1–4C)alkoxycarbonyl or oxo (to form an N-oxide).

In another aspect is provided a compound of the formula (I), or apharmaceutically-acceptable salt, or an in-vivo-hydrolysable esterthereof,

wherein:

-   R1 is selected from a substituent from the group-   (R1a) wherein R1 is halogen, (1–4C)alkoxy, (2–4C)alkenyloxy,    (2–4C)alkenyl, (2–4C)alkynyl, (3–6C)cycloalkyl, (3–6C)cycloalkenyl,    amino, (1–4C)alkylamino, di-(1–4C)alkylamino, (2–4C)alkenylamino,    (1–4C)alkylcarbonylamino, (1–4C)alkylthiocarbonylamino,-   (1–4C)alkyl-OCO—NH—, (1–4C)alkyl-NH—CO—NH—, (1–4C)alkyl-NH—CS—NH—,    (1–4C)alkyl-SO₂—NH— or (1–4C)alkyl-S(O)_(q)— (wherein q is 0, 1 or    2);-   or R1 is selected from the group-   (R1b) wherein R1 is a (1–4C)alkyl group which is substituted by one    substituent selected from hydroxy, (1–4C)alkoxy, amino, cyano,    azido, (2–4C)alkenyloxy, (1–4C)alkylcarbonyl, (1–4C)alkoxycarbonyl,    (1–4C)alkylamino, (2–4C)alkenylamino,    (1–4C)alkyl-SO₂—NH—(1–4C)alkylcarbonylamino,    (1–4C)alkylthiocarbonylamino,-   (1–4C)alkyl-OCO—NH—, (1–4C)alkyl-NH—CO—NH—, (1–4C)alkyl-NH—CS—NH—,    (1–4C)alkyl-SO₂—NH—, (1–4C)alkyl-S(O)_(q)— (wherein q is 0, 1 or 2),    (3–6C)cycloalkyl, (3–6C)cycloalkenyl, or an N-linked 5-membered    heteroaryl ring, which ring contains either (i) 1 to 3 further    nitrogen heteroatoms or (ii) a further heteroatom selected from O    and S together with an optional further nitrogen heteroatom; which    ring is optionally substituted on a carbon atom by an oxo or thioxo    group; and/or the ring is optionally substituted on a carbon atom by    1 or 2 (1–4C)alkyl groups; and/or on an available nitrogen atom    (provided that the ring is not thereby quaternised) by (1–4C)alkyl;-   or R1 is selected from a group of formula (R1c1) to (R1c3)-   (R1c1) a fully saturated 4-membered monocyclic ring containing 1 or    2 heteroatoms independently selected from O, N and S (optionally    oxidised), and linked via a ring nitrogen or carbon atom; or-   (R1c2) a saturated or unsaturated 5-membered monocyclic ring    containing 1 heteroatom selected from O, N and S (optionally    oxidised), and linked via a ring nitrogen atom if the ring is not    thereby quaternised, or a ring carbon atom; or-   (R1c3) a saturated or unsaturated 6- to 8-membered monocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N and S    (optionally oxidised), and linked via a ring nitrogen atom if the    ring is not thereby quaternised, or a ring carbon atom;    wherein said rings in (R1c1) to (R1c3) are optionally substituted on    an available carbon atom by 1 or 2 substituents independently    selected from hydroxy, (1–4C)alkoxy, amino, cyano, azido,    (2–4C)alkenyloxy, (1–4C)alkylcarbonyl, (1–4C)alkoxycarbonyl,    (1–4C)alkylamino, (2–4C)alkenylamino, (1–4C)alkyl-SO₂—NH—,    (1–4C)alkylcarbonylamino, (1–4C)alkylthiocarbonylamino,    (1–4C)alkyl-OCO—NH—, (1–4C)alkyl-NH—CO—NH—, (1–4C)alkyl-NH—CS—NH—,    (1–4C)alkyl-SO₂—NH—, (1–4C)alkyl-S(O)_(q)— (wherein q is 0, 1 or 2),    (3–6C)cycloalkyl or (3–6C)cycloalkenyl;-   or R1 is selected from the group-   (R1d) cyano, nitro, azido, formyl, (1–4C)alkylcarbonyl or    (1–4C)alkoxycarbonyl; and wherein at each occurrence of an R1    substituent containing an alkyl, alkenyl, alkynyl, cycloalkyl or    cycloalkenyl moiety in (R1a), (R1b) or (R1c1) to (R1c3) each such    moiety is optionally further substituted on an available carbon atom    with one or more substituents independently selected from F and Cl    and/or by one cyano group;-   R² and R³ are independently hydrogen or fluoro;    and wherein all other groups, variables and substituents are as    hereinbefore defined in the first aspect.

It will be noted that in the groups (Ia) to (If) there is no substituentin the position adjacent to the nitrogen link.

In this specification, where it is stated that a ring may be linked viaan sp² carbon atom it is to be understood that the ring is linked viaone of the carbon atoms in a C═C double bond.

In this specification the term ‘alkyl’ includes straight chained andbranched structures. For example, (1–6C)alkyl includes propyl, isopropyland tert-butyl. However, references to individual alkyl groups such as“propyl” are specific for the straight chained version only, andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. A similar conventionapplies to other radicals, for example halo(1–4C)alkyl includes1-bromoethyl and 2-bromoethyl.

There follow particular and suitable values for certain substituents andgroups which may be referred to in this specification. These values maybe used where appropriate with any of the definitions and embodimentsdisclosed hereinbefore, or hereinafter.

Examples of (1–4C)alkyl and (1–5C)alkyl include methyl, ethyl, propyl,isopropyl and t-butyl; examples of (1–6C)alkyl include methyl, ethyl,propyl, isopropyl, t-butyl, pentyl and hexyl; examples of (1–10C)alkylinclude methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyland nonyl; examples of (1–4C)alkanoylamino-(1–4C)alkyl includeformamidomethyl, acetamidomethyl and acetamidoethyl; examples ofhydroxy(1–4C)alkyl and hydroxy(1–6C)alkyl include hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of(1–4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl andpropoxycarbonyl; examples of 2-((1–4C)alkoxycarbonyl)ethenyl include2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of2-cyano-2-((1–4C)alkyl)ethenyl include 2-cyano-2-methylethenyl and2-cyano-2-ethylethenyl; examples of 2-nitro-2-((1–4C)alkyl)ethenylinclude 2-nitro-2-methylethenyl and 2-nitro-2-ethylethenyl; examples of2-((1–4C)alkylaminocarbonyl)ethenyl include2-(methylaminocarbonyl)ethenyl and 2-(ethylaminocarbonyl)ethenyl;examples of (2–4C)alkenyl include allyl and vinyl; examples of(2–4C)alkynyl include ethynyl and 2-propynyl; examples of (1–4C)alkanoylinclude formyl, acetyl and propionyl; examples of (1–4C)alkoxy includemethoxy, ethoxy and propoxy; examples of (1–6C)alkoxy and (1–10C)alkoxyinclude methoxy, ethoxy, propoxy and pentoxy; examples of(1–4C)alkylthio include methylthio and ethylthio; examples of(1–4C)alkylamino include methylamino, ethylamino and propylamino;examples of di-((1–4C)alkyl)amino include dimethylamino,N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino anddipropylamino; examples of halo groups include fluoro, chloro and bromo;examples of (1–4C)alkylsulfonyl include methylsulfonyl andethylsulfonyl; examples of (1–4C)alkoxy-(1–4C)alkoxy and(1–6C)alkoxy-(1–6C)alkoxy include methoxymethoxy, 2-methoxyethoxy,2-ethoxyethoxy and 3-methoxypropoxy; examples of(1–4C)alkoxy-(1–4C)alkoxy-(1–4C)alkoxy include 2-(methoxymethoxy)ethoxy,2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and2-(2-ethoxyethoxy)ethoxy; examples of (1–4C)alkylS(O)₂amino includemethylsulfonylamino and ethylsulfonylamino; examples of(1–4C)alkanoylamino and (1–6C)alkanoylamino include formamido, acetamidoand propionylamino; examples of (1–4C)alkoxycarbonylamino includemethoxycarbonylamino and ethoxycarbonylamino; examples ofN-(1–4C)alkyl-N-(1–6C)alkanoylamino include N-methylacetamido,N-ethylacetamido and N-methylpropionamido; examples of(1–4C)alkylS(O)_(p)NH— wherein p is 1 or 2 include methylsulfinylamino,methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examplesof (1–4C)alkylS(O)_(p)((1–4C)alkyl)N— wherein p is 1 or 2 includemethylsulfinylmethylamino, methylsulfonylmethylamino,2-(ethylsulfinyl)ethylamino and 2-(ethylsulfonyl)ethylamino; examples offluoro(1–4C)alkylS(O)_(p)NH— wherein p is 1 or 2 includetrifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examplesof fluoro(1–4C)alkylS(O)_(p)((1–4C)alkyl)NH— wherein p is 1 or 2 includetrifluoromethylsulfinylmethylamino andtrifluoromethylsulfonylmethylamino examples of(1–4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl andethoxy(hydroxy)phosphoryl; examples of di-(1–4C)alkoxyphosphoryl includedi-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl;examples of (1–4C)alkyls(O)_(q)— wherein q is 0, 1 or 2 includemethylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl andethylsulfonyl; examples of phenylS(O)_(q) and naphthylS(O)_(q)— whereinq is 0, 1 or 2 are phenylthio, phenylsulfinyl, phenylsulfonyl andnaphthylthio, naphthylsulfinyl and naphthylsulfonyl respectively;examples of benzyloxy-(1–4C)alkyl include benzyloxymethyl andbenzyloxyethyl; examples of a (3–4C)alkylene chain are trimethylene ortetramethylene; examples of (1–6C)alkoxy-(1–6C)alkyl includemethoxymethyl, ethoxymethyl and 2-methoxyethyl; examples ofhydroxy-(2–6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy;examples of (1–4C)alkylamino-(2–6C)alkoxy include 2-methylaminoethoxyand 2-ethylaminoethoxy; examples of di-(1–4C)alkylamino-(2–6C)alkoxyinclude 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples ofphenyl(1–4C)alkyl include benzyl and phenethyl; examples of(1–4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl;examples of di((1–4C)alkyl)carbamoyl include di(methyl)carbamoyl anddi(ethyl)carbamoyl; examples of hydroxyimino(1–4C)alkyl includehydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl;examples of (1–4C)alkoxyimino include methoxyimino and ehtoxyimino;examples of (1–4C)alkoxyimino-(1–4C)alkyl include methoxyiminomethyl,ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl;examples of halo(1–4C)alkyl include, halomethyl, 1-haloethyl,2-haloethyl, and 3-halopropyl; examples of nitro(1–4C)alkyl includenitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples ofamino(1–4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and3-aminopropyl; examples of cyano(1–4C)alkyl include cyanomethyl,1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of(1–4C)alkanesulfonamido include methanesulfonamido andethanesulfonamido; examples of (1–4C)alkylaminosulfonyl includemethylaminosulfonyl and ethylaminosulfonyl; and examples ofdi-(1–4C)alkylaminosulfonyl include dimethylaminosulfonyl,diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl; examples of(1–4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy andpropylsulfonyloxy; examples of (1–4C)alkanoyloxy include acetoxy;examples of (1–4C)alkylaminocarbonyl include methylaminocarbonyl andethylaminocarbonyl; examples of di((1–4C)alkyl)aminocarbonyl includedimethylaminocarbonyl and diethylaminocarbonyl; examples of(3–8C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl; examples of (4–7C)cycloalkyl include cyclobutyl, cyclopentyland cyclohexyl; examples of di(N-(1–4C)alkyl)aminomethylimino includedimethylaminomethylimino and diethylaminomethylimino.

Particular values for AR2 include, for example, for those AR2 containingone heteroatom, furan, pyrrole, thiophene; for those AR2 containing oneto four N atoms, pyrazole, imidazole, pyridine, pyrimidine, pyrazine,pyridazine, 1,2,3- & 1,2,4-triazole and tetrazole; for those AR2containing one N and one O atom, oxazole, isoxazole and oxazine; forthose AR2 containing one N and one S atom, thiazole and isothiazole; forthose AR2 containing two N atoms and one S atom, 1,2,4- and1,3,4-thiadiazole.

Particular examples of AR2a include, for example, dihydropyrrole(especially 2,5-dihydropyrrol-4-yl) and tetrahydropyridine (especially1,2,5,6-tetrahydropyrid-4-yl).

Particular examples of AR2b include, for example, tetrahydrofuran,pyrrolidine, morpholine (preferably morpholino), thiomorpholine(preferably thiomorpholino), piperazine (preferably piperazino),imidazoline and piperidine, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl,1,3-dioxan-5-yl and 1,4-dioxan-2-yl.

Particular values for AR3 include, for example, bicyclic benzo-fusedsystems containing a 5- or 6-membered heteroaryl ring containing onenitrogen atom and optionally 1–3 further heteroatoms chosen from oxygen,sulfur and nitrogen. Specific examples of such ring systems include, forexample, indole, benzofuran, benzothiophene, benzimidazole,benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline,quinoxaline, quinazoline, phthalazine and cinnoline.

Other particular examples of AR3 include 5/5-, 5/6 and 6/6 bicyclic ringsystems containing heteroatoms in both of the rings. Specific examplesof such ring systems include, for example, purine and naphthyridine.

Further particular examples of AR3 include bicyclic heteroaryl ringsystems with at east one bridgehead nitrogen and optionally a further1–3 heteroatoms chosen from oxygen, sulfur and nitrogen. Specificexamples of such ring systems include, for example,3H-pyrrolo[1,2-a]pyrrole, pyrrolo[2,1-b]thiazole,1H-imidazo[1,2-a]pyrrole, 1H-imidazo[1,2-a]imidazole,1H,3H-pyrrolo[1,2-c]oxazole, 1H-imidazo[1,5-a]pyrrole,pyrrolo[1,2-b]isoxazole, imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole,indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrazine,pyrrolo[1,2-a]pyrimidine, pyrido[2,1-c]-s-triazole,s-triazole[1,5-a]pyridine, imidazo[1,2-c]pyrimidine,imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine,imidazo[1,5-a]pyrazine, imidazo[1,5-a]pyrimidine,imidazo[1,2-b]-pyridazine, s-triazolo[4,3-a]pyrimidine,imidazo[5,1-b]oxazole and imidazo[2,1-b]oxazole. Other specific examplesof such ring systems include, for example, [1H]-pyrrolo[2,1-c]oxazine,[3H]-oxazolo[3,4-a]pyridine, [6H]-pyrrolo[2,1-c]oxazine andpyrido[2,1-c][1,4]oxazine. Other specific examples of 5/5-bicyclic ringsystems are imidazooxazole or imidazothiazole, in particularimidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, imidazo[5,1-b]oxazole orimidazo[2,1-b]oxazole.

Particular examples of AR3a and AR3b include, for example, indoline,1,3,4,6,9,9a-hexahydropyrido[2,1c][1,4]oxazin-8-yl,1,2,3,5,8,8a-hexahydroimidazo[1,5a]pyridin-7-yl,1,5,8,8a-tetrahydrooxazolo[3,4a]pyridin-7-yl,1,5,6,7,8,8a-hexahydrooxazolo[3,4a]pyridin-7-yl,(7aS)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl,(7aS)[5H]-1,2,3,7a-tetrahydropyrrolo[1,2c]imidazol-6-yl,(7aR)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl,[3H,5H]-pyrrolo[1,2-c]oxazol-6-yl,[5H]-2,3-dihydropyrrolo[1,2-c]imidazol-6-yl,[3H,5H]-pyrrolo[1,2-c]thiazol-6-yl,[3H,5H]-1,7a-dihydropyrrolo[1,2-c]thiazol-6-yl,[5H]-pyrrolo[1,2-c]imidazol-6-yl,[1H]-3,4,8,8a-tetrahydropyrrolo[2,1-c]oxazin-7-yl,[3H]-1,5,8,8a-tetrahydrooxazolo[3,4-a]pyrid-7-yl,[3H]-5,8-dihydroxazolo[3,4-a]pyrid-7-yl and5,8-dihydroimidazo[1,5-a]pyrid-7-yl.

Particular values for AR4 include, for example, pyrrolo[a]quinoline,2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline,1H-pyrrolo[1,2-a]benzimidazole, 9H-imidazo[1,2-a]indole,5H-imidazo[2,1-a]isoindole, 1H-imidazo[3,4-a]indole,imidazo[1,2-a]quinoline, imidazo[2,1-a]isoquinoline,imidazo[1,5-a]quinoline and imidazo[5,1-a]isoquinoline.

The nomenclature used is that found in, for example, “HeterocyclicCompounds (Systems with bridgehead nitrogen), W. L. Mosby (IntersciencePublishers Inc., New York), 1961, Parts 1 and 2.

Where optional substituents are listed such substitution is preferablynot geminal disubstitution unless stated otherwise. If not statedelsewhere, suitable optional substituents for a particular group arethose as stated for similar groups herein.

Preferable optional substituents on Ar2b as 1,3-dioxolan-4-yl,1,3-dioxan-4-yl, 1,3-dioxan-5-yl or 1,4-dioxan-2-yl are mono- ordisubstitution by substituents independently selected from (1–4C)alkyl(including geminal disubstitution), (1–4C)alkoxy, (1–4C)alkylthio,acetamido, (1–4C)alkanoyl, cyano, trifluoromethyl and phenyl].

Preferable optional substituents on CY1 & CY2 are mono- ordisubstitution by substituents independently selected from (1–4C)alkyl(including geminal disubstitution), hydroxy, (1–4C)alkoxy,(1–4C)alkylthio, acetamido, (1–4C)alkanoyl, cyano, and trifluoromethyl.

Suitable pharmaceutically-acceptable salts include acid addition saltssuch as methanesulfonate, fumarate, hydrochloride, citrate, maleate,tartrate and (less preferably) hydrobromide. Also suitable are saltsformed with phosphoric and sulfuric acid. In another aspect suitablesalts are base salts such as an alkali metal salt for example sodium, analkaline earth metal salt for example calcium or magnesium, an organicamine salt for example triethylamine, morpholine, N-methylpiperidine,N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine,tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such aslysine. There may be more than one cation or anion depending on thenumber of charged functions and the valency of the cations or anions. Apreferred pharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, saltswhich are less soluble in the chosen solvent may be preferred whetherpharmaceutically-acceptable or not.

The compounds of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). A prodrug may be used to alter or improvethe physical and/or pharmacokinetic profile of the parent compound andcan be formed when the parent compound contains a suitable group orsubstituent which can be derivatised to form a prodrug. Examples ofpro-drugs include in-vivo hydrolysable esters of a compound of theformula (I) or a pharmaceutically-acceptable salt thereof.

Various forms of prodrugs are known in the art, for examples see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309–396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Prodrugs”, by H. Bundgaard p. 113–191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1–38 (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988); and-   e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An in-vivo hydrolysable ester of a compound of the invention or apharmaceutically-acceptable salt thereof containing a carboxy or hydroxygroup is, for example, a pharmaceutically-acceptable ester which ishydrolysed in the human or animal body to produce the parent alcohol.

Suitable pharmaceutically-acceptable esters for carboxy include(1–6C)alkoxymethyl esters for example methoxymethyl,(1–6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, (3–8C)cycloalkoxycarbonyloxy(1–6C)alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-onylmethyl esters forexample 5-methyl-1,3-dioxolan-2-ylmethyl; and(1–6C)alkoxycarbonyloxyethyl esters for example1-methoxycarbonyloxyethyl and may be formed at any carboxy group in thecompounds of this invention.

Suitable pro-drugs for pyridine derivatives include acyloxymethylpyridinium salts eg halides; for example a pro-drug such as:

An in-vivo hydrolysable ester of a compound of the invention or apharmaceutically-acceptable salt thereof containing a hydroxy group orgroups includes inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters) and α-acyloxyalkyl ethers and relatedcompounds which as a result of the in-vivo hydrolysis of the esterbreakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkylethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Aselection of in-vivo hydrolysable ester forming groups for hydroxyinclude (1–10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyland phenylacetyl, (1–10C)alkoxycarbonyl (to give alkyl carbonateesters), di-(1–4C)alkylcarbamoyl andN-(di-(1–4C)alkylaminoethyl)-N-(1–4C)alkylcarbamoyl (to givecarbamates), di-(1–4C)alkylaminoacetyl, carboxy(2–5C)alkylcarbonyl andcarboxyacetyl. Examples of ring substituents on phenylacetyl and benzoylinclude chloromethyl or aminomethyl, (1–4C)alkylaminomethyl anddi-((1–4C)alkyl)aminomethyl, and morpholino or piperazino linked from aring nitrogen atom via a methylene linking group to the 3- or 4-positionof the benzoyl ring. Other interesting in-vivo hydrolysable estersinclude, for example, R^(A)C(O)O(1–6C)alkyl-CO— (wherein R^(A) is forexample, optionally substituted benzyloxy-(1–4C)alkyl, or optionallysubstituted phenyl; suitable substituents on a phenyl group in suchesters include, for example, 4-(1–4C)piperazino-(1–4C)alkyl,piperazino-(1–4C)alkyl and morpholino-(1–4C)alkyl.

Suitable in-vivo hydrolysable esters of a compound of the formula (I)are described as follows. For example, a 1,2-diol may be cyclised toform a cyclic ester of formula (PD1) or a pyrophosphate of formula(PD2), and a 1,3-diol may be cyclised to form a cyclic ester of theformula (PD3):

Esters of compounds of formula (I) wherein the HO— function/s in (PD1),(PD2) and (PD3) are protected by (1–4C)alkyl, phenyl or benzyl areuseful intermediates for the preparation of such pro-drugs.

Further in-vivo hydrolysable esters include phosphoramidic esters, andalso compounds of invention in which any free hydroxy groupindependently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0)ester of the formula (PD4):

For the avoidance of doubt, phosphono is —P(O)(OH)₂;(1–4C)alkoxy(hydroxy)-phosphoryl is a mono-(1–4C)alkoxy derivative of—O—P(O)(OH)₂; and di-(1–4C)alkoxyphosphoryl is a di-(1–4C)alkoxyderivative of —O—P(O)(OH)₂.

Useful intermediates for the preparation of such esters includecompounds containing a group/s of formula (PD4) in which either or bothof the —OH groups in (PD1) is independently protected by (1–4C)alkyl(such compounds also being interesting compounds in their own right),phenyl or phenyl-(1–4C)alkyl (such phenyl groups being optionallysubstituted by 1 or 2 groups independently selected from (1–4C)alkyl,nitro, halo and (1–4C)alkoxy).

Thus, prodrugs containing groups such as (PD1), (PD2), (PD3) and (PD4)may be prepared by reaction of a compound of invention containingsuitable hydroxy group/s with a suitably protected phosphorylating agent(for example, containing a chloro or dialkylamino leaving group),followed by oxidation (if necessary) and deprotection.

Other suitable prodrugs include phosphonooxymethyl ethers and theirsalts, for example a prodrug of R—OH such as:

When a compound of invention contains a number of free hydroxy group,those groups not being converted into a prodrug functionality may beprotected (for example, using a t-butyl-dimethylsilyl group), and laterdeprotected. Also, enzymatic methods may be used to selectivelyphosphorylate or dephosphorylate alcohol functionalities.

Where pharmaceutically-acceptable salts of an in-vivo hydrolysable estermay be formed this is achieved by conventional techniques. Thus, forexample, compounds containing a group of formula (PD1), (PD2), (PD3)and/or (PD4) may ionise (partially or fully) to form salts with anappropriate number of counter-ions. Thus, by way of example, if anin-vivo hydrolysable ester prodrug of a compound of invention containstwo (PD4) groups, there are four HO—P— functionalities present in theoverall molecule, each of which may form an appropriate salt (i.e. theoverall molecule may form, for example, a mono-, di-, tri- ortetra-sodium salt).

The compounds of the present invention have a chiral centre at the C-5position of the oxazolidinone ring. The pharmaceutically activeenantiomer is of the formula (IA):

The present invention includes the pure enantiomer depicted above ormixtures of the 5R and 5S enantiomers, for example a racemic mixture. Ifa mixture of enantiomers is used, a larger amount (depending upon theratio of the enantiomers) will be required to achieve the same effect asthe same weight of the pharmaceutically active enantiomer. Theenantiomer depicted above may be the 5(R) or 5(S) enantiomer dependingon the nature of the N-HET group (for example, when —N-HET is imidazoleit is the 5(S) enantiomer).

Furthermore, some compounds of the formula (I) may have other chiralcentres, for example, certain sulfoxide compounds may be chiral at thesulfur atom. It is to be understood that the invention encompasses allsuch optical and diastereo-isomers, and racemic mixtures, that possessantibacterial activity. It is well known in the art how to prepareoptically-active forms (for example by resolution of the racemic form byrecrystallisation techniques, by chiral synthesis, by enzymaticresolution, by biotransformation or by chromatographic separation) andhow to determine antibacterial activity as described hereinafter.

Furthermore, some compounds of the formula (I), for example certainsulfoxide compounds may exist as cis- and trans-isomers. It is to beunderstood that the invention encompasses all such isomers, and mixturesthereof, that possess antibacterial activity.

The invention relates to all tautomeric forms of the compounds of theformula (I) that possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I)may exhibit polymorphism, and that the invention encompasses all suchforms which possess antibacterial activity.

As stated before, we have discovered a range of compounds that have goodactivity against a broad range of Gram-positive pathogens, includingorganisms known to be resistant to most commonly used antibiotics, andto certain fastidious Gram negative strains such as H. influenzae and M.catarrhalis. They have good physical and/or pharmacokinetic propertiesin general, and favourable toxicological and MAO profiles.

Particularly preferred compounds of the invention comprise a compound offormula (I), or a pharmaceutically-acceptable salt or an in-vivohydrolysable ester thereof, wherein the substituents Q, HET (which mayalso be described as —N-HET herein), T and other substituents mentionedabove have values disclosed hereinbefore, or any of the following values(which may be used where appropriate with any of the definitions andembodiments disclosed hereinbefore or hereinafter):

In one embodiment of the invention are provided compounds of formula(I), in an alternative embodiment are providedpharmaceutically-acceptable salts of compounds of formula (I), in afurther alternative embodiment are provided in-vivo hydrolysable estersof compounds of formula (I), and in a further alternative embodiment areprovided pharmaceutically-acceptable salts of in-vivo hydrolysableesters of compounds of formula (I).

In another embodiment of the invention are provided compounds of formula(I), or a pharmaceutically-acceptable salt or an in-vivo hydrolysableester thereof, in which Q, HET (which may also be described as —N-HETherein) and other substituents mentioned above have the values disclosedhereinbefore, and T is as defined hereinbefore and hereinafter for (TA),(TB) and (TD) (i.e. in this embodiment T is not (TC) or (TE)).

In another embodiment of the invention are provided compounds of formula(I), or a pharmaceutically-acceptable salt or an in-vivo hydrolysableester thereof, in which Q, HET (which may also be described as —N-HETherein) and other substituents mentioned above have the values disclosedhereinbefore, and T is as defined hereinbefore and hereinafter for (TC),particularly TC4.

In another embodiment of the invention are provided compounds of formula(I), or a pharmaceutically-acceptable salt or an in-vivo hydrolysableester thereof, in which Q, HET (which may also be described as —N-HETherein) and other substituents mentioned above have the values disclosedhereinbefore, and T is as defined hereinbefore and hereinafter for (TA).

In another embodiment of the invention are provided compounds of formula(I), or a pharmaceutically-acceptable salt or an in-vivo hydrolysableester thereof, in which Q, HET (which may also be described as —N-HETherein) and other substituents mentioned above have the values disclosedhereinbefore, and T is as defined hereinbefore and hereinafter for (TA)and (TC).

In a further embodiment of the invention are provided compounds offormula (I), or a pharmaceutically-acceptable salt or an in-vivohydrolysable ester thereof, in which Q, HET (which may also be describedas —N-HET herein), T and other substituents mentioned above have thevalues disclosed hereinbefore and R1 is selected from the group (R1b).

Preferably Q is selected from Q1, Q2, Q4 and Q6; especially Q1 and Q2;and most preferably Q is Q1.

In one embodiment R1 has values (R1a) to (R1c1).

Preferable R1 groups are those of (R1a) and (R1b).

In (R1b) the substituted (1–4C)alkyl group is preferably a substitutedmethyl group.

Preferable (R1) groups provided by optional F and/or Cl and/or one cyanofurther substituents in (R1a) and (R1b) are, for example, R1 astrifluoromethyl, —CHF₂, —CH₂F, —CH₂CN, —CF₂NH(1–4C)alkyl, —CF₂CH₂OH,—CH₂OCF₃, —CH₂OCHF₂, —CH₂OCH₂F, —NHCF₂CH₃.

In one aspect R1 is preferably selected from a substituent from thegroups R1a, R1b and R1 d wherein:

-   (R1a) halogen, hydroxy, (1–4C)alkoxy, (2–4C)alkenyloxy,    (2–4C)alkenyl, (2–4C)alkynyl (optionally substituted on the terminal    carbon by CH₂═CH—, di(1–4C)alkylamino, AR2, AR2a or AR2b),    (3–6C)cycloalkyl, (3–6C)cycloalkenyl, (1–4C)alkyl-S(O)q- (wherein q    is 0), amino, (1–4C)alkylcarbonylamino, (1–4C)alkylamino,    di-(i-4C)alkylamino and (2–4C)alkenylamino;-   (R1b) a (1–4C)alkyl group which is substituted by one substituent    selected from hydroxy, halo, (1–4C)alkoxy, amino, (1–4C)alkylamino,    di-(1–4C)alkylamino, (1–4C)alkyl-S(O)q- (wherein q is 0, 1 or 2),    cyano and azido, (3–6C)cycloalkyl, AR1-S(O)q- (wherein q is 0, 1 or    2 and AR1 is defined hereinbelow), AR2-S(O)q- (wherein q is 0, 1 or    2), AR2a-S(O)q- (wherein q is 0, 1 or 2), benzyl-S(O)q- (wherein q    is 0, 1 or 2), (1–4C)alkyl-OCO—NH—, (1–4C)alkyl-NHCO—O—,    (1–4C)alkylaminocarbonyl, di(1–4C)alkylaminocarbonyl and    H₂NC(═NH)S—;-   (R1d) cyano, nitro, azido, formyl, (1–4C)alkylcarbonyl,    (1–4C)alkoxycarbonyl, H₂NC(O)—, ((1–4C)alkyl)NHC(O)—;    and wherein at each occurrence of an R1 substituent containing an    alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety in (R1a)    or (R1b) each such moiety is optionally further substituted on an    available carbon atom with one, two, three or more substituents    independently selected from F, Cl, Br, OH and CN.

In another aspect R1 is preferably selected from a substituent from thegroups R1a, R1b and R1d, wherein:

-   (R1a) halogen, hydroxy, (1–4C)alkoxy, (2–4C)alkenyl, (2–4C)alkynyl,    -ethynyl-ethene, -ethynyl-AR2, -ethynyl-AR2a, -but-2-ynyl-4-AR2a,    -but-2-ynyl-4-AR2b, -but-2-ynyl-4-di(1–4C)alkylamino,    (3–6C)cycloalkyl, (1–4C)alkyl-S(O)q- (wherein q is 0),    (1–4C)alkylcarbonylamino and amino,-   (R1b) a (1–4C)alkyl group which is substituted by one substituent    selected from hydroxy, halo, (1–4C)alkoxy, amino,    di(1–4C)alkylamino, cyano, azido, (1–4C)alkyl-S(O)q- (wherein q is    0, 1 or 2), AR2-S(O)q- (wherein q is 0), benzyl-S(O)q- (wherein q is    0), (1–4C)alkyl-OCO—NH—, (1–4C)alkyl-NHCO—O—,    di(1–4C)alkylaminocarbonyl and H₂NC(═NH)S—;-   (R1d) cyano, nitro, formyl, (1–4C)alkoxycarbonyl and H₂NC(O)—;    and wherein at each occurrence of an R1 substituent containing an    alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety in (R1a)    or (R1b) each such moiety is optionally further substituted on an    available carbon atom with one, two or three substituents    independently selected from F, Cl, Br, OH and CN.    When R1a is ethynyl-AR2, conveniently AR2 is a 5-membered ring,    particularly AR2 is oxazolyl, isoxazolyl, thiazolyl or thiadiazolyl.    When R1a is -ethynyl-AR2a or -but-2-ynyl-4-AR2a, conveniently AR2a    is a 5 membered ring, particularly AR2a as 3-pyrroline, 2H-pyrrole    or pyrazoline.    When R1a is -but-2-ynyl-4-AR2b, conveniently AR2b a 6-membered ring    such as morpholine.

In a further aspect R1 is most preferably

-   (a) hydrogen; or-   (b) halogen, in particular fluorine, chlorine, or bromine; or-   (c) cyano; or-   (d) monosubstituted (1–4C)alkyl, in particular fluoromethyl,    choromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl;    or-   (e) disubstituted (1–4C)alkyl, for example difluoromethyl, or-   (f) trisubstituted (1–4C)alkyl, for example trifluoromethyl; or-   (g) ethynyl or substituted ethynyl; or-   (h) nitro

In (TAb), preferred are (TAb1) to (TAb5), and especially (TAb2), (TAb3)and/or (TAb5), most especially (TAb2) and (TAb5). The above preferredvalues of (TAb) are particularly preferred when present in Q1 or Q2,especially Q1.

In (TAb) it is to be understood that when a value for —X¹— is a two-atomlink and is written, for example, as —CH₂NH— it is the left hand part(—CH₂— here) which is bonded to the group of formula (TAb1) to (TAb6)and the right hand part (—NH— here) which is bonded to —Y— in thedefinition in (TAbc). Similarly, when —Y¹— is a two-atom link and iswritten, for example, as —CONH— it is the left hand part of —Y¹— (—CO—here) which is bonded to the right hand part of —X¹—, and the right handpart of —Y¹— (—NH— here) which is bonded to the AR2, AR2a, AR2b, AR3,AR3a or AR3b moiety in the definition in (TAbc).

In one embodiment, in (TAb) preferably R⁶ is hydrogen or (1–4C)alkyl,and R⁴ and R⁵ are independently selected from hydrogen, cyano, formyl,bromo, hydroxymethyl, thiomethyl, (1–4C)alkyl (particularly methyl) andhydroxyimino or one of R⁴ and R⁵ is selected from group (TAba1). Mostpreferable is (TAb2) and/or (TAb5) with such preferable substituents.

In another embodiment in (TAb) preferably R⁶ is hydrogen or (1–4C)alkyl,and R⁴ and R⁵ are independently selected from hydrogen, cyano, formyl,bromo, hydroxymethyl, (1–4C)alkyl or one of R⁴ and R⁵ is selected fromgroup (TAba1). Most preferable is (TAb2) and/or (TAb5) with suchpreferable substituents.

In another embodiment, in (TAb) preferably R⁶ is hydrogen or(1–4C)alkyl, and R⁴ and R⁵ are independently selected from hydrogen,cyano, formyl, bromo, hydroxymethyl, thiomethyl, (1–4C)alkyl(particularly methyl) and hydroxyimino. Most preferable is (TAb2) and/or(TAb5) with such preferable substituents.

In another embodiment, in (TAb), R⁶ is hydrogen and R⁴ and R⁵ areindependently selected from hydrogen and methyl.

In (TC), for the avoidance of doubt, ( )_(m1), ( )_(n1) and ( )_(o1)indicate (—CH₂—)_(m1), (—CH₂—)_(n1) and (—CH₂—)_(o1) respectively(optionally substituted as described above).

In the definition of (TC1) to (TC4), in an alternative embodiment>A₃-B₃— is not >N—CH₂— in (TC1) to (TC3).

In the above definition of (TC1) to (TC4) and of the further optionalsubstituents:

-   (i) ARc is preferably AR2, and in one embodiment the further    optional substituents are preferably not selected from the values    listed for Rc.-   (ii) A preferred value for G is >N(Rc) or >C(R¹¹)(R12). Also    preferred is G as O or S, particularly in (TC4) when Rp is hydrogen.-   (iii) Preferred is (TC4) as piperazinyl, morpholino or    thiomorpholino or as tetrahydropyridin-4-yl.-   (iv)>A₃-B₃— is preferably >C(Rq)-CH(Rr)- in (TC1) to (TC3).

Particularly preferred values for the optional substituents and groupsdefined in (TC) are rings of formula (TC5) to (TC11), particularly whenpresent in Q1 or Q2, especially Q1:

wherein Rc has any of the values listed hereinbefore or hereinafter.

Especially preferred are (TC5), (TC6), (TC7) and (TC9), most especially(TC5) in which Rc has any of the values listed hereinbefore orhereinafter (especially R¹³CO— with the preferable R¹³ values givenhereinafter). In (TC5) Rc is preferably selected from the group (Rc2),especially R¹³CO— with the preferable R¹³ values given hereinafter. In(TC7) Rc is preferably selected from group (Rc3) or (Rc4).

For (TC), further preferred values for the optional substituents andgroups defined in (TC) are rings of formula (TC12) and (TC13),particularly when present in Q1 or Q2, especially Q1:

wherein G is —O—, —S—, —SO—, —SO₂— or >N(Rc) and Rc, o1 and n1 have anyof the values defined herein.

Preferably (TC12) is (TC12a), (TC12b), (TC12c) or (TC12d) and preferably(TC13) is (TC13a), particularly when present in Q1 or Q2, especially Q1:

wherein m is 0, 1 or 2.

In (TDa), particularly preferred values are when present in Q1 or Q2,especially Q1.

In (TDb) it will be appreciated that unstable anti-Bredt compounds arenot contemplated in this definition (i.e. compounds with stuctures(TDb3), (TDb4), (TDb7), (TDb8), (TDb9), (TDb12), (TDb13) and (TDb14) inwhich an sp² carbon atom is directed towards a bridgehead position).

In (TDb), particularly preferred values of (TDb) are the followingstructures of formula (TDb4), (TDb8) and/or (TDb9); wherein Rc has anyof the values listed hereinbefore or hereinafter. The values of (TDb)are particularly preferred when present in Q1 or Q2, especially Q1.

In (TE1) to (TE3), preferred values for the groups defined in (TE) aredefined by formulae (TE1a, b), (TE2a) and (TE3a), particularly whenpresent in Q1 or Q2, especially Q1:

wherein G is —O—, —S—, —SO— or —SO₂—.

Preferably (T) is (TC12a), (TC12b) or (TAb2) particularly when presentin Q1 or Q2, especially Q1.

Preferable values for other substituents (which may be used whereappropriate with any of the definitions and embodiments disclosedhereinbefore or hereinafter) are:

-   (a) —N-HET is preferably of formula (Ic), (Id) or (If).-   (b) In one aspect preferably one of R² and R³ is hydrogen and the    other fluoro. In another aspect both R² and R³ are fluoro.-   (c) In another aspect one of R² and R³ is hydrogen or fluoro and the    other is selected from Cl, CF₃, Me, Et, OMe and SMe.-   (d) In (TC4) preferably >A₃-B₃— is >C═CH— or >N—CH₂—.-   (e) Preferably Rc is R¹³CO— and preferably R¹³ is    (1–4C)alkoxycarbonyl, hydroxy(1–4C)alkyl, (1–4C)alkyl (optionally    substituted by one or two hydroxy groups, or by an (1–4C)alkanoyl    group), (1–4C)alkylamino, dimethylamino(1–4C)alkyl,    (1–4C)alkoxymethyl, (1–4C)alkanoylmethyl,    (1–4C)alkanoyloxy(1–4C)alkyl, (1–5C)alkoxy or 2-cyanoethyl.-   (f) More preferably R¹³ is 1,2-dihydroxyethyl,    1,3-dihydroxyprop-2-yl, 1,2,3-trihydroxyprop-1-yl, methoxycarbonyl,    hydroxymethyl, methyl, methylamino, dimethylaminomethyl,    methoxymethyl, acetoxymethyl, methoxy, methylthio, naphthyl,    tert-butoxy or 2-cyanoethyl.-   (g) Particularly preferred as R¹³ is 1,2-dihydroxyethyl,    1,3-dihydroxyprop-2-yl or 1,2,3-trihydroxyprop-1-yl.-   (h) In another aspect preferably R¹³ is (1–10C)alkyl [optionally    substituted by one or more hydroxy] or R¹⁴C(O)O(1–6C)alkyl.

For compounds of formula (I) preferred values for Rc are those in group(Rc2) when present in any of the definitions herein containing Rc—forexample when present in compounds in which there is a (TC5) or (TC9)ring system.

In the definition of (Rc2c) the AR2a, AR2b, AR3a and AR3b versions ofAR2 and AR3 containing groups are preferably excluded.

Where the number of optional substituents on a group is not otherwisepreferably defined, the preferable number of optional substituents isone.

Particularly preferred compounds of the present invention are of theformula (IB):

wherein —N-HET is 1,2,3-triazol-1-yl or tetrazol-2-yl;

-   R1 is selected from (R1a) or (R1b);-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from (TAb1 to 6), (TC5), (TC7), (TC9), (TC12), (TC13)    and (TE1) to (TE3); or in-vivo hydrolysable esters or    pharmaceutically-acceptable salts thereof.

Further particularly preferred compounds of the present invention are ofthe formula (IB) defined above, wherein —N-HET is 1,2,3-triazol-1-yl ortetrazol-2-yl;

-   R1 is selected from (R1d);-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from (TAb1 to 6), (TC5), (TC7), (TC9), (TC12), (TC13)    and (TE1) to (TE3); or in-vivo hydrolysable esters or    pharmaceutically-acceptable salts thereof.

Further particularly preferred compounds of the present invention are ofthe formula (IB) defined above, wherein —N-HET is 1,2,3-triazol-1-yl ortetrazol-2-yl;

-   R1 is selected from (R1a), (R1b) and (R1d);-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from (TAb1 to 6), (TC12a) and (TC12b); or in-vivo    hydrolysable esters or pharmaceutically-acceptable salts thereof.

Further particularly preferred compounds of the present invention are ofthe formula (IB) defined above, wherein —N-HET is 1,2,3-triazol-1-yl ortetrazol-2-yl;

-   R1 is selected from (R1a), (R1b) and (R1d);-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from (TAb2), (TAb3), (TAb5), (TAb6), (TC5), (TC12a),    (TC12b), (TC12d) and (TC13a); or in-vivo hydrolysable esters or    pharmaceutically-acceptable salts thereof.

Further particularly preferred compounds of the present invention are ofthe formula (EB) defined above, wherein —N-HET is 1,2,3-triazol-1-yl ortetrazol-2-yl;

-   R1 is selected from (R1a), (R1b) and (R1d);-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from (TAb2), (TC12a) and (TC12b); or in-vivo    hydrolysable esters or pharmaceutically-acceptable salts thereof.

Further particularly preferred compounds of the present invention are ofthe formula (IB) defined above wherein R1 is a methyl group from (R1b),substituted with any of those substituents defined herein in (R1b), orin-vivo hydrolysable esters or pharmaceutically-acceptable saltsthereof.

Further especially preferred compounds of the invention are of theformula (IB) defined above wherein T is selected from (TAb2 & 5), (TC5),(TC9), (TC12a to d), (TC13a), (TE1a & b), (TE2a) and (TE3a); or in-vivohydrolysable esters or pharmaceutically-acceptable salts thereof.

In the above aspects and preferred compounds of formula (IB), in (TC5),(TC7), (TC9), preferably Rc is as defined in (Rc2) and especially R¹³CO—wherein R¹³ is preferably (1–4C)alkoxycarbonyl, hydroxy(1–4C)alkyl,(1–4C)alkyl (optionally substituted by one or two hydroxy groups, or byan (1–4C)alkanoyl group), (1–4C)alkylamino, dimethylamino(1–4C)alkyl,(1–4C)alkoxymethyl, (1–4C)alkanoylmethyl, (1–4C)alkanoyloxy(1–4C)alkyl,(1–5C)alkoxy or 2-cyanoethyl.

In all of the above aspects and preferred compounds of formula (IB),in-vivo hydrolysable esters are preferred where appropriate, especiallyphosphoryl esters (as defined by formula (PD4) with npd as 1).

In all of the above definitions the preferred compounds are as shown informula (IA), i.e. the pharmaceutically active enantiomer.

Process Section:

In a further aspect the present invention provides a process forpreparing a compound of formula (I) or a pharmaceutically-acceptablesalt or an in-vivo hydrolysable ester thereof. It will be appreciatedthat during certain of the following processes certain substituents mayrequire protection to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject, for example, ‘Protective Groups in Organic Synthesis’ byTheodora Green (publisher: John Wiley & Sons). Protecting groups may beremoved by any convenient method as described in the literature or knownto the skilled chemist as appropriate for the removal of the protectinggroup in question, such methods being chosen so as to effect removal ofthe protecting group with minimum disturbance of groups elsewhere in themolecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulfuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Resins may also be used as a protecting group.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

A compound of the formula (I), or a pharmaceutically-acceptable salt oran in vivo hydrolysable ester thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a compound of theformula (I), or a pharmaceutically-acceptable salt or an in vivohydrolysable ester thereof, are provided as a further feature of theinvention and are illustrated by the following representative examples.Necessary starting materials may be obtained by standard procedures oforganic chemistry (see, for example, Advanced Organic Chemistry(Wiley-Interscience), Jerry March). The preparation of such startingmaterials is described within the accompanying non-limiting Examples (inwhich, for example, 3,5-difluorophenyl, 3-fluorophenyl and(des-fluoro)phenyl containing intermediates may all be prepared byanalagous procedures; or by alternative procedures—for example, thepreparation of (T group)-(fluoro)phenyl intermediates by reaction of a(fluoro)phenylstannane with, for example, a pyran or(tetrahydro)pyridine compound, may also be prepared by anion chemistry(see, for example, WO97/30995). Alternatively, necessary startingmaterials are obtainable by analogous procedures to those illustratedwhich are within the ordinary skill of an organic chemist. Informationon the preparation of necessary starting materials or related compounds(which may be adapted to form necessary starting materials) may also befound in the following Patent and Application Publications, the contentsof the relevant process sections of which are hereby incorporated hereinby reference:

WO99/02525; WO98/54161; WO97/37980; WO97/30981 (& U.S. Pat. No.5,736,545); WO97/21708 (& U.S. Pat. No. 5,719,154); WO97/10223;WO97/09328; WO96/35691; WO96/23788; WO96/15130; WO96/13502; WO95/25106(& U.S. Pat. No. 5,668,286); WO95/14684 (& U.S. Pat. No. 5,652,238);WO95/07271 (& U.S. Pat. No. 5,688,792); WO94/13649; WO94/01 110;WO93/23384 (& U.S. Pat. No. 5,547,950 & U.S. Pat. No. 5,700,799);WO93/09103 (& U.S. Pat. No. 5,565,571, U.S. Pat. No. 5,654,428, U.S.Pat. No. 5,654,435, U.S. Pat. No. 5,756,732 & U.S. Pat. No. 5,801,246);U.S. Pat. No. 5,231,188; U.S. Pat. No. 5,247,090; U.S. Pat. No.5,523,403; WO97/27188; WO97/30995; WO97/31917; WO98/01447; WO98/01446;WO99/10342; WO99/10343; WO99/11642; WO99/64416; WO99/64417; WO00/21960;WO 01/40222; WO01/81350 and WO01/98297; European Patent Application Nos.0,359,418 and 0,609,905; 0,693,491 A1 (& U.S. Pat. No. 5,698,574);0,694,543 A1 (& AU 24985/95); 0,694,544 A1 (& CA 2,154,024); 0,697,412A1 (& U.S. Pat. No. 5,529,998); 0,738,726 A1 (& AU 50735/96); 0,785,201A1 (& AU 10123/97); German Patent Application Nos. DE 195 14 313 A1 (&U.S. Pat. No. 5,529,998); DE 196 01 264 A1 (& AU 10098/97); DE 196 01265 A1 (& AU 10097/97); DE 196 04 223 A1 (& AU 12516/97); DE 196 49 095A1 (& AU 12517/97).

The following Patent and Application Publications may also provideuseful information and the contents of the relevant process sections arehereby incorporated herein by reference:

FR 2458547; FR 2500450 (& GB 2094299, GB 2141716 & U.S. Pat. No.4,476,136); DE 2923295 (& GB 2028306, GB 2054575, U.S. Pat. No.4,287,351, U.S. Pat. No. 4,348,393, U.S. Pat. No. 4,413,001, U.S. Pat.No. 4,435,415 & U.S. Pat. No. 4,526,786), DE 3017499 (& GB 2053196, U.S.Pat. No. 4,346,102 & U.S. Pat. No. 4,372,967); U.S. Pat. No. 4,705,799;European Patent Application Nos. 0,312,000; 0,127,902; 0,184,170;0,352,781; 0,316,594;

The skilled organic chemist will be able to use and adapt theinformation contained and referenced within the above references, andaccompanying Examples therein and also the Examples herein, to obtainnecessary starting materials, and products.

Process Section:

Thus, the present invention also provides that the compounds of theformula (I) and pharmaceutically-acceptable salts and in vivohydrolysable esters thereof, can be prepared by a process (a) to (h) asfollows (wherein the variables are as defined above unless otherwisestated):

-   (a) by modifying a substituent in, or introducing a new substituent    into, the substituent group R1 of HET of another compound of formula    (I)—for instance by (i) displacement of a functional group from a    compound of formula (I) by another functional group, (ii) by    oxidation or (iii) reduction of a compound of formula (I), by (iv)    addition of a reagent to or (v) elimination of a reagent from a    compound of formula (I), by (vi) metathesis of a compound of    formula (I) into a modified compound of formula (I), or by (vii)    rearrangement of a compound of formula (I) to an isomeric compound    of formula (I); or by modifying a substituent in, or introducing a    new substituent into, the group Q of another compound of formula    (I)—for instance by (i) displacement of a functional group from a    compound of formula (I) by another functional group, (ii) by    oxidation or (iii) reduction of a compound of formula (I), by (iv)    addition of a reagent to or (v) elimination of a reagent from a    compound of formula (I), by (vi) metathesis of a compound of    formula (I) into a modified compound of formula (I), or by (vii)    rearrangement of a compound of formula (I) to an isomeric compound    of formula (I) (Scheme I shows examples drawn from the range of    suitable methods); or-   (b) by reaction of a compound of formula (II):

wherein Y is a displaceable group (which may be preformed, such aschloro or mesylate, or generated in-situ, for example under Mitsunobuconditions) with a compound of the formula (III):HET  (III)wherein HET (of formula (Ia) to (If), already substituted and optionallyprotected) is HET-H free-base form or HET-anion formed from the freebase form (Scheme II shows examples drawn from the range of suitablemethods); or

-   (c) by reaction of a compound of the formula (IV):    Q-Z  (IV)    wherein Z is an isocyanate, amine or urethane group with an epoxide    of the formula (V) wherein the epoxide group serves as a leaving    group at the terminal C-atom and as a protected hydroxy group at the    internal C-atom; or with a related compound of formula (VI) where    the hydroxy group at the internal C-atom is conventionally protected    e.g. with an acetyl group and where the leaving group Y at the    terminal C-atom is a conventional leaving group e.g. a chloro- or    mesyloxy-group;

(Scheme III shows examples drawn from the range of suitable methods), or(d) (i) by coupling, using catalysis by transition metals such aspalladium(0), of a compound of formula (VII):

wherein Y′ is a group HET as hereinbefore defined, X is a replaceablesubstituent—such as chloride, bromide, iodide, ortrifluoromethylsulfonyloxy;with a compound of the formula (VIII), or an analogue thereof, which issuitable to give a T substituent as defined by (TA)-(TE), in which thelink is via an sp² carbon atom (D=CH═C-Lg where Lg is a leaving groupsuch as chloride, bromide, iodide, or trifluoromethylsulfonyloxy; or asin the case of reactions carried out under Heck reaction conditions Lgmay also be hydrogen) or in which the link is via an N atom (D=NH)

where T₁ and T₂ may be the same or different or may together with D forma ring of type T as hereinbefore described (Scheme IV shows examplesdrawn from the range of suitable methods);

-   (d) (ii) by coupling, using catalysis by transition metals such as    palladium(0), of a compound of formula (VIIA):

wherein Y′ is a group HET as hereinbefore defined, with a compound[Aryl]-X, where X is a replaceable substituent—such as chloride,bromide, iodide, or trifluoromethylsulfonyloxy, or an analogue thereof(Scheme IV shows an example drawn from the range of suitable methods);

-   (e) Where N-HET is 1,2,3-triazole there is the additional    possibility by cycloaddition via the azide (wherein Y in (II) is    azide), with a substituted acetylene or a masked acetylene (such as    a vinyl sulfone, a nitroloefin, or an enamine, or a substituted    cyclohexa-1,4-diene derivative (Scheme II shows examples drawn from    the range of suitable methods);-   (f) Where N-HET is 1,2,3-triazole there is the additional    possibility of synthesis by reaction of a compound of formula (II)    where Y═NH₂ (primary amine) with a compound of formula (IX), namely    the arenesulfonylhydrazone of a methyl ketone that is further    geminally substituted on the methyl group by two substituents (Y′    and Y″) capable of being eliminated from this initial, and the    intermediate, substituted hydrazones as HY′ and HY″ (or as conjugate    bases thereof) (Scheme V shows an example drawn from the range of    suitable methods);

-   (g) where N-HET is 1,2,3-triazole there is the additional    possibility of regioselective. synthesis by cycloaddition via the    azide (wherein Y in (II) is azide) with a terminal alkyne using    Cu(I) catalysis in e.g. aqueous alcoholic solution at ambient    temperatures to give 4-substituted 1,2,3-triazoles;

-   (h) where N-HET is 1,2,3-triazole there is the additional    possibility of regioselective synthesis by cycloaddition via the    azide (wherein Y in (II) is azide) with an    alpha-halovinylsulfonylchloride (XIII);    and thereafter if necessary: (i) removing any protecting    groups; (ii) forming a pharmaceutically-acceptable salt; (iii)    forming an in-vivo hydrolysable ester.

The main synthetic routes are illustrated in Schemes (I) to (VII) below(with Q as phenyl, and T, R1, R2, R3, and A defined with reference toanalogous substituents defined elsewhere herein). The compounds of theinvention may be prepared by analogous chemistry adapted from theseSchemes. Schemes (II), (VI), and (VII) also show the preparation of1,2,3-triazoles via the azide (prepared from the relevant hydroxycompound) and the amine (prepared e.g. from the azide) respectively.

Deprotection, salt formation or in-vivo hydrolysable ester formation mayeach be provided as a specific final process step.

The N-linked hetereocycle can of course be prepared early in the overallsynthesis, and then other functional groups changed.

Where Y is a displaceable group, suitable values for Y are for example,a halogeno or sulfonyloxy group, for example a chloro, bromo,methanesulfonyloxy or toluene-4-sulfonyloxy group.

General guidance on reaction conditions and reagents may be obtained inAdvanced Organic Chemistry, 4^(th) Edition, Jerry March (publisher: J.Wiley & Sons), 1992. Necessary starting materials may be obtained bystandard procedures of organic chemistry, such as described in thisprocess section, in the Examples section or by analogous procedureswithin the ordinary skill of an organic chemist. Certain references arealso provided which describe the preparation of certain suitablestarting materials, for example International Patent ApplicationPublication No. WO 97/37980, the contents of which are incorporated hereby reference. Processes analogous to those described in the referencesmay also be used by the ordinary organic chemist to obtain necessarystarting materials.

(a) Methods for converting substituents into other substituents areknown in the art. For example an alkylthio group may be oxidised to analkylsulfinyl or alkysulfonyl group, a cyano group reduced to an aminogroup, a nitro group reduced to an amino group, a hydroxy groupalkylated to a methoxy group, a hydroxy group thiomethylated to anarylthiomethyl or a heteroarylthiomethyl group (see, for example, Tet.Lett., 585, 1972), a carbonyl group converted to a thiocarbonyl group(eg. using Lawsson's reagent) or a bromo group converted to an alkylthiogroup. It is also possible to convert one Rc group into another Rc groupas a final step in the preparation of a compound of the formula (I), forexample, acylation of a group of formula (TC5) wherein Rc is hydrogen.

(b)(i) Reaction (b)(i) (in which Y is initially hydroxy) is performedunder Mitsunobu conditions, for example, in the presence oftri-n-butylphosphine and diethyl azodicarboxylate (DEAD) in an organicsolvent such as THF, and in the temperature range 0° C.–60° C., butpreferably at ambient temperature. Details of Mitsunobu reactions arecontained in Tet. Letts., 31, 699, (1990); The Mitsunobu Reaction, D. L.Hughes, Organic Reactions, 1992, Vol. 42, 335–656 and Progress in theMitsunobu Reaction, D. L. Hughes, Organic Preparations and ProceduresInternational, 1996, Vol. 28, 127–164.

Compounds of the formula (II) wherein Y is hydroxy may be obtained asdescribed in the references cited herein (particularly in the sectionproceeding the discussion of protecting groups), for example, byreacting a compound of the formula (X) with a compound of formula (XI):

wherein R²¹ is (1–6C)alkyl or benzyl and R²² is (1–4C)alkyl or—S(O)_(n)(1–4C)alkyl where n is 0, 1 or 2. Preferably R²² is(1–4C)alkyl.

In particular, compounds of the formula (II), (X) and (XI) may beprepared by the skilled man, for example as described in InternationalPatent Application Publication Nos. WO95/07271, WO97/27188, WO 97/30995,WO 98/01446 and WO 98/01447, the contents of which are herebyincorporated by reference, and by analogous processes.

If not commercially available, compounds of the formula (III) may beprepared by procedures which are selected from standard chemicaltechniques, techniques which are analogous to the synthesis of known,structurally similar compounds, or techniques which are analogous to theprocedures described in the Examples. For example, standard chemicaltechniques are as described in Houben Weyl, Methoden der OrganischeChemie, E8a, Pt.I (1993), 45–225, B. J. Wakefield.

(b)(ii) Reactions (b)(ii) are performed conveniently in the presence ofa suitable base such as, for example, an alkali or alkaline earth metalcarbonate, alkoxide or hydroxide, for example sodium carbonate orpotassium carbonate, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo-[5.4.0]undec-7-ene, thereaction is also preferably carried out in a suitable inert solvent ordiluent, for example methylene chloride, acetonitrile, tetrahydrofuran,1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulfoxide at and at a temperature inthe range 25–60° C.

When Y is chloro, the compound of the formula (II) may be formed byreacting a compound of the formula (II) wherein Y is hydroxy (hydroxycompound) with a chlorinating agent. For example, by reacting thehydroxy compound with thionyl chloride, in a temperature range ofambient temperature to reflux, optionally in a chlorinated solvent suchas dichloromethane or by reacting the hydroxy compound with carbontetrachloride/triphenyl phosphine in dichloromethane, in a temperaturerange of 0° C. to ambient temperature. A compound of the formula (II)wherein Y is chloro or iodo may also be prepared from a compound of theformula (II) wherein Y is mesylate or tosylate, by reacting the lattercompound with lithium chloride or lithium iodide and crown ether, in asuitable organic solvent such as THF, in a temperature range of ambienttemperature to reflux.

When Y is (1–4C)alkanesulfonyloxy or tosylate the compound (II) may beprepared by reacting the hydroxy compound with (1–4C)alkanesulfonylchloride or tosyl chloride in the presence of a mild base such astriethylamine or pyridine.

When Y is a phosphoryl ester (such as (PhO)₂—P(O)—O—) or Ph₂–—P(O)—O—the compound (II) may be prepared from the hydroxy compound understandard conditions.

(c) Reaction (c) is performed under conditions analogous to thosedescribed in the following references which disclose how suitable andanalogous starting materials may be obtained.

Reaction (c) is especially suitable for compounds in which HET-H is aweakly acidic heterocycle (such as, for example, triazole or tetrazole).

Compounds of the formula Q-Z wherein Z is an isocyanate may be preparedby the skilled chemist, for example by analogous processes to thosedescribed in Walter A. Gregory et al in J. Med. Chem. 1990, 33,2569–2578 and Chung-Ho Park et al in J. Med. Chem. 1992, 35, 1156–1165.Compounds of the formula Q-Z wherein Z is a urethane may be prepared bythe skilled chemist, for example by analogous processes to thosedescribed in International Patent Application Publication Nos. WO97/30995 and WO 97/37980.

A similar reaction to reaction (c) may be performed in which Q-Z whereinZ is a amine group is reacted with the epoxide (optionally in thepresence of an organic base), and the product is reacted with, forexample, phosgene to form the oxazolidinone ring. Such reactions and thepreparation of starting materials in within the skill of the ordinarychemist with reference to the above-cited documents disclosing analogousreactions and preparations.

Epoxides of the formula (V) may be prepared from the correspondingcompound of formula (XII):

Certain such epoxide and alkene intermediates are novel and are providedas a further feature of the invention. Asymmetric epoxidation may beused to give the desired optical isomer. Compounds of formula (VI) maybe obtained from epoxides of formula (V); alternatively compounds offormula (VI) may be used as precursors for epoxides of formula (V)according to the relative ease of synthesis in each case. The skilledchemist will appreciate that the epoxides of formula (V) and thecompounds of formula (VI) are structurally equivalent and the choicebetween them will be made on the grounds of availability, convenience,and cost.

-   (d) The transition metal catalysed coupling reaction to form a C—C    or N—C bond from the corresponding aryl derivatives and the arenes,    heteroarenes, olefins, alkynes, or amines is performed under    conventional conditions (see for instance J. K. Stille, Angew. Chem.    Int. Ed. Eng., 1986, 25, 509–524; N. Miyaura and A. Suzuki, Chem.    Rev., 1995, 95, 22457–2483; D. Baranano, G. Mann, and J. F. Hartwig,    Current Org. Che., 1997, 1, 287–305; S. P. Stanforth, Tetrahedron,    1998, 54, 263–303). The reaction d (ii) may be conveniently carried    out under the conditions described Tetrahedron Letters (2001), 42    (22), 3681–3684, or in the analogous conventional conditions    described in the above mentioned literature. In such a procedure a    preferred variation of X may be bromine.-   (e) The cycloaddition reaction to form 1,2,3 triazoles from the    corresponding azide is performed under conventional conditions.    Compounds of the formula (II) wherein Y is azide may be obtained as    described in the references cited herein (particularly in the    section proceeding the discussion of protecting groups), for example    from the corresponding compounds in which Y is hydroxy or mesylate.-   (f) The reaction of amines of formula (I, Y═NH2) with arenesulfonyl    hydrazones to form 1,2,3 triazoles may be carried out as described    in the literature (Sakai, Kunikazu; Hida, Nobuko; Kondo and Kiyosi    “Reactions of α-polyhalo ketone tosylhydrazones with sulfide ion and    primary amines. Cyclization to 1,2,3-thiadiazoles and    1,2,3-triazoles.” Bull. Chem. Soc. Jpn. (1986), 59 (1), 179–83;    Sakai, Kunikazu; Tsunemoto, Daiei; Kobori, Takeo; Kondo, Kiyoshi;    Hida and Nobuko: “1,2,3-Trihetero 5-membered heterocyclic compounds”    EP103840 A2 19840328). The leaving groups Y, Y′ may be chloro or any    other group capable of being eliminated from the arenesulfonyl    hydrazone during the reaction with the amine. The skilled chemist    will also appreciate that a similar reaction may be used to produce    other substituted triazoles suitable for incorporation into related    processes such as reaction with compounds of formula (IV) in process    (c).-   (g) The reaction of azides of formula (II, Y═N₃) with as terminal    alkynes using Cu(I) catalysis to give regioselectively 4-substituted    1,2,3-triazole compounds of formula (I) may be carried out as    described in the literature (for instance V. V. Rostovtsev, L. G.    Green, V.V. Fokin, and K. B. Sharpless, Angew. Chem. Int. Ed., 2002,    41, 2596–2599).-   (h) The reaction of alkylazides with 1-halovinylsulfonyl chlorides    at a temperature between 0° C. and 100° C. either neat or in an    inert diluent such as chlorobenzene, chloroform or dioxan gives    4-halogenated 1,2,3-triazole compounds of formula (I). The reaction    may be applied to 1-fluoro-, 1-chloro-, 1-bromo-, or    1-iodo-vinylsulfonylchlorides.

The removal of any protecting groups, the formation of apharmaceutically-acceptable salt and/or the formation of an in vivohydrolysable ester are within the skill of an ordinary organic chemistusing standard techniques. Furthermore, details on the these steps, forexample the preparation of in-vivo hydrolysable ester prodrugs has beenprovided in the section above on such esters, and in certain of thefollowing non-limiting Examples.

When an optically active form of a compound of the formula (I) isrequired, it may be obtained by carrying out one of the above proceduresusing an optically active starting material (formed, for example, byasymmetric induction of a suitable reaction step), or by resolution of aracemic form of the compound or intermediate using a standard procedure,or by chromatographic separation of diastereoisomers (when produced).Enzymatic techniques may also be useful for the preparation of opticallyactive compounds and/or intermediates.

Similarly, when a pure regioisomer of a compound of the formula (I) isrequired, it may be obtained by carrying out one of the above proceduresusing a pure regioisomer as a starting material, or by resolution of amixture of the regioisomers or intermediates using a standard procedure.

According to a further feature of the invention there is provided acompound of the formula (I), or a pharmaceutically-acceptable salt, orin-vivo hydrolysable ester thereof for use in a method of treatment ofthe human or animal body by therapy.

According to a further feature of the present invention there isprovided a method for producing an antibacterial effect in a warmblooded animal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a compound of thepresent invention, or a pharmaceutically-acceptable salt, or in-vivohydrolysable ester thereof.

The invention also provides a compound of the formula (I), or apharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof,for use as a medicament; and for use as an anti-bacterial agent; and theuse of a compound of the formula (I) of the present invention, or apharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof,in the manufacture of a medicament for use in the production of anantibacterial effect in a warm blooded animal, such as man.

In order to use a compound of the formula (I), an in-vivo hydrolysableester or a pharmaceutically-acceptable salt thereof, including apharmaceutically-acceptable salt of an in-vivo hydrolysable ester,(hereinafter in this section relating to pharmaceutical composition “acompound of this invention”) for the therapeutic (includingprophylactic) treatment of mammals including humans, in particular intreating infection, it is normally formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula(I), an in-vivo hydrolysable ester or a pharmaceutically-acceptable saltthereof, including a pharmaceutically-acceptable salt of an in-vivohydrolysable ester, and a pharmaceutically-acceptable diluent orcarrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration aseye-drops, for administration by inhalation (for example as a finelydivided powder or a liquid aerosol), for administration by insufflation(for example as a finely divided powder) or for parenteraladministration (for example as a sterile aqueous or oily solution forintravenous, subcutaneous, sub-lingual, intramuscular or intramusculardosing or as a suppository for rectal dosing).

In addition to the compounds of the present invention, thepharmaceutical composition of this invention may also contain (iethrough co-formulation) or be co-administered (simultaneously,sequentially or separately) with one or more known drugs selected fromother clinically useful antibacterial agents (for example, β-lactams,macrolides, quinolones or aminoglycosides) and/or other anti-infectiveagents (for example, an antifungal triazole or amphotericin). These mayinclude carbapenems, for example meropenem or imipenem, to broaden thetherapeutic effectiveness. Compounds of this invention may also beco-formulated or co-administered withbactericidal/permeability-increasing protein (BPI) products or effluxpump inhibitors to improve activity against gram negative bacteria andbacteria resistant to antimicrobial agents.

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents. A pharmaceutical composition to be dosedintravenously may contain advantageously (for example to enhancestability) a suitable bactericide, antioxidant or reducing agent, or asuitable sequestering agent.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol. Solubility enhancing agents,for example cyclodextrins may be used.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 50 mgto 5 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 200 mg to about 2 g of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 1 mg and 1 g of a compound of thisinvention, preferably between 100 mg and 1 g of a compound. Especiallypreferred is a tablet or capsule which contains between 50 mg and 800 mgof a compound of this invention, particularly in the range 100 mg to 500mg.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection, forexample an injection which contains between 0.1% w/v and 50% w/v(between 1 mg/ml and 500 mg/ml) of a compound of this invention.

Each patient may receive, for example, a daily intravenous, subcutaneousor intramuscular dose of 0.5 mgkg⁻¹ to 20 mgkg⁻¹ of a compound of thisinvention, the composition being administered 1 to 4 times per day. Inanother embodiment a daily dose of 5 mgkg⁻¹ to 20 mgkg⁻¹ of a compoundof this invention is administered. The intravenous, subcutaneous andintramuscular dose may be given by means of a bolus injection.Alternatively the intravenous dose may be given by continuous infusionover a period of time. Alternatively each patient may receive a dailyoral dose which may be approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day.

In the above other, pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

Biological Activity:

The pharmaceutically-acceptable compounds of the present invention areuseful antibacterial agents having a good spectrum of activity in vitroagainst standard Gram-positive organisms, which are used to screen foractivity against pathogenic bacteria. Notably, thepharmaceutically-acceptable compounds of the present invention showactivity against enterococci, pneumococci and methicillin resistantstrains of S. aureus and coagulase negative staphylococci, together withhaemophilus and moraxella strains. The antibacterial spectrum andpotency of a particular compound may be determined in a standard testsystem.

The (antibacterial) properties of the compounds of the invention mayalso be demonstrated and assessed in-vivo in conventional tests, forexample by oral and/or intravenous dosing of a compound to awarm-blooded mammal using standard techniques.

The following results were obtained on a standard in-vitro test system.The activity is described in terms of the minimum inhibitoryconcentration (MIC) determined by the agar-dilution technique with aninoculum size of 10⁴ CFU/spot. Typically, compounds are active in therange 0.01 to 256 μg/ml.

Staphylococci were tested on agar, using an inoculum of 10⁴ CFU/spot andan incubation temperature of 37° C. for 24 hours—standard testconditions for the expression of methicillin resistance.

Streptococci and enterococci were tested on agar supplemented with 5%defibrinated horse blood, an inoculum of 10⁴ CFU/spot and an incubationtemperature of 37° C. in an atmosphere of 5% carbon dioxide for 48hours—blood is required for the growth of some of the test organisms.Fastidious Gram negative organisms were tested in Mueller-Hinton broth,supplemented with hemin and NAD, grown aerobically for 24 hours at 37°C., and with an innoculum of 5×10⁴ CFU/well.

For example, the following results were obtained for the compound ofExample 3:

Organism MIC (μg/ml) Staphylococcus aureus: MSQS 4 MRQR 8 Streptococcuspneumoniae 2 Streptococcus pyogenes 2 Haemophilus influenzae 2 Moraxellacatarrhalis 4 MSQS = methicillin sensitive and quinolone sensitive MRQR= methicillin resistant and quinolone resistant

The activity of the compounds of the invention against MAO-A was testedusing a standard in-vitro assay based on human liver enzyme expressed inyeast as described in Biochem. Biophys. Res. Commun. 1991, 181,1084–1088. The compounds of the invention showed decreased MAO-A potencycompared with analogues from the known art with C-5 side chains such asacetamidomethyl or unsubstituted azolylmethyl or hydroxymethyl. Thecompounds of the invention showed decreased MAO-A potency compared withanalogues in which the HET group of formula (Ia) to (If) isunsubstituted. When Ki values were measured in such an assay as above,Example 3 showed a Ki value of >177 μg/ml.

MAO activity in general comprises activity in both MAO-A and MAO-Benzymes. The compounds of the invention in general demonstratefavourable profiles against both enzymes.

Certain intermediates and/or Reference Examples described hereinafterwithin the scope of the invention may also possess useful activity, andare provided as a further feature of the invention.

The invention is now illustrated but not limited by the followingExamples in which unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and    work-up procedures were carried out after removal of residual solids    by filtration;-   (ii) operations were carried out at ambient temperature, that is    typically in the range 18–26° C. and without exclusion of air unless    otherwise stated, or unless the skilled person would otherwise work    under an inert atmosphere;-   (iii) column chromatography (by the flash procedure) was used to    purify compounds and was performed on Merck Kieselgel silica    (Art. 9385) unless otherwise stated;-   (iv) yields are given for illustration only and are not necessarily    the maximum attainable;-   (v) the structure of the end-products of the invention were    generally confirmed by NMR and mass spectral techniques [proton    magnetic resonance spectra were generally determined in DMSO-d₆    unless otherwise stated using a Varian Gemini 2000 spectrometer    operating at a field strength of 300 MHz, or a Bruker AM250    spectrometer operating at a field strength of 250 MHz; chemical    shifts are reported in parts per million downfield from    tetramethysilane as an internal standard (δ (delta) scale) and peak    multiplicities are shown thus: s, singlet; d, doublet; AB or dd,    doublet of doublets; dt, doublet of triplets; dm, doublet of    multiplets; t, triplet, m, multiplet; br, broad; fast-atom    bombardment (FAB) mass spectral data were generally obtained using a    Platform spectrometer (supplied by Micromass) run in electrospray    and, where appropriate, either positive ion data or negative ion    data were collected];-   (vi) each intermediate was purified to the standard required for the    subsequent stage and was characterised in sufficient detail to    confirm that the assigned structure was correct; purity was assessed    by HPLC, TLC, or NMR and identity was determined by infra-red    spectroscopy (IR), mass spectroscopy or NMR spectroscopy as    appropriate;-   (vii) in which the following abbreviations may be used:

DMF is N,N-dimethylformamide; DMA is N,N-dimethylacetamide; TFA istrifluoroacetic acid; TLC is thin layer chromatography; HPLC is highpressure liquid chromatography; MPLC is medium pressure liquidchromatography; DMSO is dimethylsulfoxide; CDCl₃ is deuteratedchloroform; MS is mass spectroscopy; ESP is electrospray; EI is electronimpact; CI is chemical ionisation; APCI is atmospheric pressure chemicalionisation; NOE is nuclear Overhauser effect (NMR experiment); EtOAc isethyl acetate; MeOH is methanol.

The microwave used was a “Smith Syntheziser” made by Personal Chemistry.

EXAMPLE 1(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-carbonitrile)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one(0.21 g, 0.6 mmol) (Reference Example 1) was dissolved in dry1,4-dioxane (4 ml), 2-chloroacrylonitrile(78.7 mg, 0.9 mmol) was addedand the resulting mixture was refluxed for 12 hours under vigorousstirring. The solvent was removed under vacuum and the residue waspurified by flash chromatography on silica gel with 5% methanol indichloromethane to give the title product (0.21 g) as the only isomerisolated. WO 98/02423 describes the use of chloroacrylonitrile in the“Process For Preparing 1-Substituted 4-cyano-1,2,3 Triazoles”.

MS (ESP): 402.12 (MH⁺) for C₁₈H₁₆FN₅O₃S ¹H-NMR(DMSO-d₆) δ: 2.57 (m, 1H);2.97 (m, 2H); 3.13 (m, 1H); 3.39 (m, 1H); 3.67 (m, 1H); 3.94 (m, 1H);4.29 (dd, 1H); 4.97 (d, 2H); 5.20 (m, 1H); 5.85 (m, 1H); 7.30 (dd, 1H);7.41 (t, 1H); 7.47 (dd, 1H); 9.15 (s, 1H).

EXAMPLE 2(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-methoxycarbonyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one(500 mg, 1.43 mmol) (Reference Example 1) was dissolved in dry1,4-dioxane (1.0 ml), 2-propynoic acid methyl ester (180 mg, 2.14 mmol)was added and the resulting mixture was refluxed for 12 hours undervigorous stirring. The solvent was removed under vacuum and the residuewas purified by flash chromatography on silica gel with 5% methanol indichloromethane to give the title product (486 mg).

MS (ESP): 435.13 (MH⁺) for C₁₉H₁₉FN₄O₅S ¹H-NMR(DMSO-d₆) δ: 2.56 (m, 1H);2.97 (m, 2H); 3.13 (m, 1H); 3.39 (m, 1H); 3.67 (m, 1H); 3.86 (s, 3H);3.96 (m, 1H); 4.27 (dd, 1H); 4.90 (d, 2H); 5.21 (m, 1H); 5.84 (m, 1H);7.31 (dd, 1H); 7.41 (t, 1H); 7.47 (dd, 1H); 8.85 (s, 1H).

EXAMPLE 3(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-azidomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(1.1 g, 2.7 mmol) (Example 4) was suspended in dichloromethane (10 ml).1,8-Diazabicyclo[5.4.0]undec-7-ene (0.71 g, 4.7 mmol) was added and thereaction mixture was cooled to −5° C. Diphenylphosphoryl azide (0.89 g,3.25 mmol) was added dropwise and it was stirred for 18 hours at roomtemperature. The solvent was evaporated and the residue chromatographedon silica gel with 5% methanol in dichloromethane to give the titleproduct (1.02 g).

MS (ESP): 432.17 (MH⁺) for C₁₈H₁₈FN₇O₃S ¹H-NMR (DMSO-d₆) δ: 2.58 (m,1H); 2.85–3.00 (m, 2H); 3.12 (m, 1H); 3.40 (m, 1H); 3.67 (m, 1H); 3.92(dd, 1H); 4.28 (dd, 1H); 4.53 (s, 2H); 4.86 (m, 2H); 5.18 (m, 1H); 5.84(m, 1H); 7.29 (dd, 1H); 7.40 (dd, 1H); 7.46 (dd, 1H); 8.25 (s, 1H).

EXAMPLE 4(5R)-3-[4-(1(R,S)-Oxo-3,6dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one(3 g, 8.56 mmol) (Reference Example 1) was dissolved in refluxingtoluene (25 ml). Propargyl alcohol (1.93 g, 34.35 mmol) was added andthe resulting 2-phase mixture was refluxed for 18 hours under vigorousstirring. The solvent was removed under vacuum and the residuechromatographed on silicagel with 10% methanol in chloroform to give 1.1g of the title compound, next to 1.2 g of the corresponding5-(hydroxymethyl) regioisomer.

MS (ESP): 407.14 (MH⁺) for C₁₈H₁₉FN₄O₄S ¹H-NMR (DMSO-d₆) δ: 2.58 (m,1H); 2.85–3.00 (m, 2H); 3.14 (m, 1H); 3.40 (m, 1H); 3.68 (m, 1H); 3.92(dd, 1H); 4.27 (dd, 1H); 4.53 (d, 2H); 4.82 (m, 2H); 5.15 (m, 1H); 5.23(dd, 1H, exchangeable); 5.84 (m, 1H); 7.31 (dd, 1H); 7.40 (dd, 1H); 7.48(dd, 1H); 8.03 (s, 1H). 4-substitution on the triazole moiety wasconfirmed by NOE experiments. The 5-hydroxymethyl regioisomer shows H-4of triazole moiety at 7.66 ppm.

EXAMPLE 5(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-trifluoromethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one(0.33 g, 1 mmol) (Reference Example 1) was dissolved in refluxingtoluene (15 ml). 3,3,3-Trifluoro-1-(phenylsulfonyl)-1-propene (0.24 g, 1mmol) was added and the resulting mixture was refluxed for 12 hoursunder vigorous stirring. The solvent was removed under vacuum and thecrude product was dissolved in methanol/ethylacetate/water (1:1:1, 30ml). Sodium periodate (0.21 g, 1 mmol) was added, the reaction mixturewas stirred at room temperature for 1 hour. It was extracted withdichloromethane (3×20 ml), the organic phase was dried over magnesiumsulfate and concentrated to dryness. This residue was purified by flashchromatography on silicagel with 5% methanol in dichloromethane to give100 mg of the title compound, next to 13 mg of the corresponding5-trifluoromethyl compound.

MS (ESP): 439.22 (MH⁺) for C₁₈H₁₆F₄N₄O₃S ¹H-NMR (CDC₃) δ: 2.75 (m, 1H);2.97 (m, 1H); 3.10 (m, 1H); 3.21 (m, 1H); 3.46 (m, 1H); 3.64 (m, 1H);3.96 (dd, 1H); 4.26 (dd, 1H); 4.80 (m, 1H); 4.90 (m, 1H); 5.12 (m, 1H);5.83 (m, 1H); 7.11 (m, 1H); 7.25 (dd, 1H); 7.37 (dd, 1H); 8.14 (s, 1H).

The 5-trifluoromethyl regioisomer shows H-4 of the triazole moiety at8.08 ppm.

REFERENCE EXAMPLE 1(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one

(5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyloxazolidin-2-one(2.3 g, 6.5 mmol) (see WO 01/81350) was dissolved inmethanol/ethylacetate (1:1, 100 ml) and sodium periodate (1.75 g, 8.2mmol) dissolved in water (20 ml) was added dropwise over 1 hour. Thereaction mixture was stirred for 7 hours at room temperature, filteredto remove most of the salts and the methanol was evaporated undervacuum. The aqueous solution thus obtained was extracted withethylacetate, dried over sodium sulfate and evaporated to dryness. Theresidue was subjected to chromatography on silica gel withacetone/hexane (2:1) to give 2.18 g of the product.

MS (ESP): 351.34 (MH⁺) for C₁₅H₁₅FN₄O₃S ¹H-NMR (DMSO-d₆) δ: 2.58 (m,1H); 2.85–3.01 (m, 2H); 3.10–3.16 (m, 1H); 3.40 (dd, 1H); 3.64–3.84 (m,4H); 4.17 (dd, 1H); 4.93 (m, 1H); 5.85 (m,1H); 7.36 (dd, 1H); 7.41 (dd,1H); 7.53 (dd, 1H).

EXAMPLE 6(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-aminomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-azidomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 3) (0.718 g, 1.66 mmol) was dissolved in 1,4-dioxane (5 ml) andhydrogenated over Pd/C (10%, wet) at normal pressure and roomtemperature for 2 days. It was filtered through a 0.45 μM membrane andthe solvent was removed under vacuum. Chromatography on silica gel withacetonitrile/water (3:1) gave 0.37 g (55%) of the title compound as acolorless amorphous solid after lyophilization.

MS (ESP): 406.12 (MH⁺) for C₁₈H₂₀FN₅O₃S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.58 (m, 1H); 2.85–3.00 (m, 2H); 3.10–3.16 (m, 1H); 3.39 (m, 1H); 3.67(m, 1H); 3.76 (s, 2H); 3.91 (dd, 1H); 4.26 (dd, 1H); 4.80 (m, 2H); 5.15(m, 1H); 5.84 (m, 1H); 7.30 (dd, 1H); 7.40 (dd, 1H); 7.47 (dd, 1H); 7.96(s, 1H).

EXAMPLE 7(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-(aminocarbonyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-methoxycarbonyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 2) (225 mg, 0.52 mmol) was dissolved in ammonia/methanolsolution (2M, 5 ml) in a sealed tube. The mixture was stirred for 48hours and the precipitate formed during the reaction was filtered andwashed with ethyl acetate to give the title compound as a colourlesssolid. Further product was obtained by concentrating the filtratefollowed by purification by chromatography on silica gel with 2.5%methanol in dichloromethane to give a combined yield of 148 mg.

MS (ESP): 420.13 (MH⁺) for C₁₈H₁₈FN₅O₄S ¹H-NMR(DMSO-d₆) δ: 2.56 (m, 1H);2.97 (m, 2H); 3.13 (m, 1H); 3.39 (m, 1H); 3.67 (m, 1H); 3.96 (m, 1H);4.27 (dd, 1H); 4.89 (d, 2H); 5.21 (m, 1H); 5.84 (m, 1H); 7.30 (dd, 1H);7.41 (t, 1H); 7.47 (dd, 1H); 7.48 (s, 1H); 7.88 (s, 1H); 8.59 (s, 1H).

EXAMPLE 8(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-(methoxycarbonyl)aminomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1(R,S)-Oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-aminomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 6) (50 mg, 0.12 mmol) was dissolved/suspended in pyridine (0.5ml), dichloromethane (2 ml) was added and the solution was cooled to−25° C. Methylcarbamylchloride (20 μl, 0.26 mmol) was added and it wasstirred for 30 minutes. The reaction was quenched with methanol (3drops) and solvent was evaporated under vacuum. Chromatography on silicagel with dichloromethane/methanol (12:1) gave 50 mg (87%) of the titlecompound as a colourless solid.

MS (ESP): 464.16 (MH⁺) for C₂₀H₂₂FN₅O₅S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.58 (m, 1H); 2.85–3.00 (m, 2H); 3.11–3.15 (m, 1H); 3.38 (m, 1H); 3.56(s, 3H); 3.67 (m, 1H); 3.90 (dd, 1H); 4.23–4.28 (m, 3H); 4.81 (m, 2H);5.15 (m, 1H); 5.84 (m, 1H); 7.30 (dd, 1H); 7.40 (dd, 1H); 7.47 (dd, 1H);7.99 (s, 1H).

EXAMPLE 9(5R)-3-[4-(1,1-Dioxo-3,6dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (Reference Example 2) (15 g, 41 mmol) wasdissolved/suspended in 2-(phenylsulfonyl)-2-propene-1-o1 (DE 2630947)(12 g, 61 mmol) and N-methylpyrrolidone (NMP, 2 ml) and stirred at 90°C. After 30 minutes more NMP (2 ml) was added and stirred for another3.5 hours. The partially solidified reaction mixture was taken up inDMF, it was filtered and then concentrated under vacuum. The resultingoil in residual DMF was chromatographed on silica gel withdichloromethane/methanol (16:1) to give 8.64 g (50%) of the titleproduct (TLC: Rf 0.3, chloroform/methanol=6:1) as a colourless solid.The corresponding 5-hydroxymethyl regioisomer was separated duringchromatography and presented a minor product (TLC: Rf 0.4,chloroform/methanol=6:1). The structures were assigned based on NOEstudies.

MS (ESP): 422.94 (MH⁺) for C₁₈H₁₉FN₄O₅S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.98 (m, 2H); 3.28–3.36 (m, 2H); 3.91–3.94 (m, 3H); 4.27 (dd, 1H); 4.54(d, 2H); 4.82 (d, 2H); 5.16 (m, 1H); 5.23 (dd, 1H); 5.84 (m, 1H); 7.30(dd, 1H); 7.41 (dd, 1H); 7.50 (dd, 1H); 8.03 (s, 1H).

REFERENCE EXAMPLE 2(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one

(5R)-3-[4-(3,6-Dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one(WO 01/81350 A1; WO 02/081470 A1) (7 g, 20.9 mmol) was dissolved indichloromethane (200 ml) and cooled to 0° C. A solution of3-chloroperbenzoic acid (15.4 g, 70%, 62.9 mmol) was added dropwise. Thetemperature was allowed to reach room temperature over 2 hours and itwas stirred for an additonal 30 minutes at room temperature. Thereaction mixture was diluted with ethyl acetate, washed with aqueoussodium thiosulfate solution, then with aqueous sodium hydrogencarbonatesolution and with water and dried over sodium sulfate. Chromatography onsilica gel with hexanes/acetone (3:2) gave 6.75 g (88%) of the titlecompound.

MS (ESP): 367.1 (MH⁺) for C₁₅H₁₅FN₄O₄S ¹H-NMR (DMSO-d) (500 MHz) δ: 2.98(m, 2H); 3.35–3.40 (m, 2H); 3.71 (dd, 1H); 3.79 (dd, 1H); 3.82 (dd, 1H);3.93 (m, 2H); 4.17 (dd, 1H); 4.93 (m, 1H); 5.84 (m, 1H); 7.37 (dd, 1H);7.42 (dd, 1H); 7.54 (dd, 1H).

EXAMPLE 10(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-bromomethyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 9) (2.05 g, 4.9 mmol) and carbon tetrabromide (1.93 g, 5.8mmol) were dissolved/suspended in dichloromethane (100 ml) and cooled to0° C. Triphenylphosphine (2.05 g, 7.8 mmol) was added and the reactionmixture was stirred for 10 minutes at 0° C. then for 20 minutes at roomtemperature. The reaction mixture was applied onto a silica gel columnand product was eluted with hexanes/acetone (1:1). Fractions containingproduct were pooled, solvent was removed under vacuum and product wasprecipitated from dichloromethane by addition of hexanes to give thetitle compound, 1.94 g (82%) as colourless needles.

MS (ESP): 485/457 (MH⁺) for C₁₈H₁₈BrFN₄O₄S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.98 (m, 2H); 3.28–3.36 (m, 2H); 3.90–3.94 (m, 3H); 4.28 (dd, 1H); 4.77(s, 2H); 4.84 (m, 2H); 5.16 (m, 1H); 5.83 (m, 1H); 7.30 (dd, 1H); 7.41(dd, 1H); 7.47 (dd, 1H); 8.26 (s, 1H).

EXAMPLE 11(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4fluoromethyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-bromomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 10) (385 mg, 0.8 mmol) was dissolved in a mixture of1-butyl-3-methyl-imidazolium tetrafluoroborate (1 ml), acetonitrile (4ml) and water (90 μl). Potassium fluoride (231 mg, 4 mmol) was added andthe reaction mixture was heated to 100° C. for 4 hours. It was dilutedwith ethylacetate and water, the organic phase was washed with water,diluted with dichloromethane and dried over sodium sulfate.Chromatography on silica gel with dichloromethane/DMF (30:1), followedby precipitation from dichloromethane/methanol gave 86 mg (26%) productas colourless needles.

MS (ESP): 424.9 (MH⁺) for C₁₈H₁₈F₂N₄O₄S ¹H-NMR (DMSO-d₆) (300 MHz) δ:2.95 (m, 2H); 3.28–3.36 (m, 2H); 3.92–3.95 (m, 3H); 4.26 (dd, 1H); 4.85(d, 2H); 5.16 (m, 1H); 5.47 (d, 2H); 5.82 (m, 1H); 7.27–7.49 (m, 3H);8.37 (d, 1H).

EXAMPLE 12(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-{[4-[(aminomethaneiminiumbromide)thiomethyl]-1,2,3-triazol-1-yl}methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-bromomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 10) (3.4 g, 7.0 mmol) and thiourea (0.54 g, 7.1 mmol) wererefluxed in ethanol (100 ml) for 2 hours under vigorous stirring. Thereaction mixture was cooled to room temperature, filtered, washed withethanol and dried under vacuum to give 3.67 g (93%) of the titlecompound as a colourless solid.

MS (ESP): 481.26 (M⁺) for C₁₉H₂₂FN₆O₄S₂ ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.94 (m, 2H); 3.29–3.39 (m, 2H); 3.74 (s, 2H); 3.87–3.92 (m, 3H); 4.25(dd, 1H); 4.56 (s, 2H); 4.83 (d, 2H); 5.13 (m, 1H); 5.81 (m, 1H); 7.27(dd, 1H); 7.39 (dd, 1H); 7.44 (dd, 1H); 8.16 (s, 1H); 9.01 (brs, 2H);9.18 (brs, 2H).

EXAMPLE 13(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(methylthio)methyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(aminomethaneiminiumbromide)thiomethyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(1 g, 1.78 mmol) (Example 12), methyl iodide (135 μl, 2.17 mmol) andtetrabutylammonium bromide (a few crystals) were vigorously stirred atroom temperature for 30 minutes under nitrogen in a mixture of benzene(10 ml) and aqueous sodium hydroxide solution (10 ml, 15%). The reactionmixture was diluted with dichloromethane, washed with 1M aqueous HCl andpotassium phosphate buffer (1M, pH 7) and dried over sodium sulfate.Chromatography on silica gel with acetone/hexanes (1.2:1) gave 0.994 gof the title compound as a colourless hard foam.

MS (ESP): 452.98 (MH⁺) for C₁₉H₂₁FN₄O₄S₂ ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.00 (s, 3H); 2.97 (m, 2H); 3.28–3.39 (m, 2H); 3.74 (s, 2H); 3.90–3.93(m, 3H); 4.27 (dd, 1H); 4.81 (d, 2H); 5.16 (m, 1H); 5.83 (m, 1H); 7.29(m, 1H); 7.40 (dd, 1H); 7.45 (m, 1H); 8.05 (s, 1H).

EXAMPLE 14(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(methylsulfonyl)methyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[[4-[(methylthio)methyl]-1,2,3-triazol-1-yl]methyl]oxazolidin-2-one(Example 13) (0.994 g, 2.2 mmol) was dissolved in dichloromethane (50ml) and cooled to 0° C. 3-Chloroperbenzoic acid (0.807 g, 70%, 3.3mmol), dissolved in dichloromethane (20 ml) was added drop wise. Thereaction mixture was then stirred for 3 hours at room temperature. Itwas diluted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution was added. The resulting precipitate was collected byfiltration, washed with sodium hydrogen carbonate solution, water andwith ethyl acetate and dried under vacuum to give 0.467 g (44%) of thetitle compound as a colourless solid.

MS (ESP): 485.23 (MH⁺) for C₁₉H₂₁FN₄O₆S₂ ¹H-NMR (DMSO-d₆) (300 MHz) δ:2.96 (m, 5H); 3.28–3.40 (m, 2H); 3.90–3.95 (m, 3H); 4.26 (dd, 1H); 4.63(s, 2H); 4.86 (d, 2H); 5.16 (m, 1H); 5.82 (m, 1H); 7.28–7.50 (m, 3H);8.24 (s, 1H).

EXAMPLE 15(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(diphenoxyphosphinyl)oxymethyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 9) (0.66 g, 1.6 mmol) was dissolved/suspended indichloromethane/pyridine (10 ml, 2:1) and it was cooled to 0° C.Diphenylphosphorochloridate (0.33 ml, 1.6 mmol) dissolved indichloromethane (2 ml) was added drop wise. The reaction mixture wasstirred for 30 minutes at 0° C. and then an additional 60 μl (0.29 mmol)of diphenylphophorochloridate was added via syringe and it was stirredfor another hour. It was quenched with phosphate buffer (pH 7), dilutedwith ethyl acetate and the organic phase was washed with water and driedover sodium sulfate. Chromatography on silica gel with acetone/hexanes(1:1) to give 0.82 g (80%) of the title compound as a hard foam.

MS (ESP): 655.05 (MH⁺) for C₃₀H₂₈FN₄O₈PS ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.94 (m, 2H); 3.29–3.34 (m, 2H); 3.90 (m, 3H); 4.12 (s, 2H); 4.24 (dd,1H); 4.83 (m, 2H); 5.14 (m, 1H); 5.39 (m, 2H); 5.80 (m, 1H); 7.19–7.30(m, 7H); 7.35–7.47 (m, 6H); 8.30 (s, 1H).

EXAMPLE 16(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-cyanomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-[[(diphenoxyphosphinyl)oxy]methyl]-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one(Example 15) (0.5 g, 0.76 mmol) and sodium cyanide (0.22 g, 4.5 mmol)were dissolved/suspended in DMF (10 ml) and it was heated to 60° C. for1.5 hours. It was diluted with ethyl acetate, washed with potassiumphosphate buffer (pH 7) and with water, and dried over sodium sulfate.Chromatography on silica gel with acetone/hexanes (1:1) gave 236 mg(72%) of the title compound as a colourless solid.

MS (ESP): 432.07 (MH⁺) for C₁₉H₁₈FN₅O₄S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.94 (m, 2H); 3.30–3.34 (m, 2H); 3.88–3.90 (m, 3H); 4.12 (s, 2H); 4.24(dd, 1H); 4.82 (d, 2H); 5.14 (m, 1H); 5.81 (m, 1H); 7.28 (dd, 1H); 7.38(dd, 1H); 7.45 (dd, 1H); 8.16 (s, 1H).

EXAMPLE 17(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-chloromethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 9) (0.65 g, 1.6 mmol) was dissolved/suspended indichloromethane/pyridine (10 ml, 2:1) and reacted withdiphenylphosphorochloridate (1 ml, 4.8 mmol) as described for Example15. The solvent was removed under vacuum, the residue taken up in DMF(10 ml) and sodium cyanide was added (5 fold excess, in an attempt tomake the cyanide). The reaction mixture was heated at 60° C. for 30minutes and then at 80° C. for one hour. It was diluted with ethylacetate, washed with water and dried over sodium sulfate. Chromatographyon silica gel with hexanes/acetone (1:1) gave 0.29 g (66%) of the titlecompound as a colourless solid.

MS (ESP): 441.02 (MH⁺) for C₁₈H₁₈ClFN₄O₄S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.98 (m, 2H); 3.29–3.37 (m, 2H); 3.90–3.95 (m, 3H); 4.28 (dd, 1H);4.84–4.87 (m, 4H); 5.17 (m, 1H); 5.84 (m, 1H); 7.30 (m, 1H); 7.41 (dd,1H); 7.47 (m, 1H); 8.27 (s, 1H).

EXAMPLE 18(5R)-3-[4-(1,1-Dioxo-tetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (0.8 g, 2.2 mmol) (Reference Example 2) andtetrahydro-2-(2-propynyloxy)-2H-pyran (1.3 ml, 9.2 mmol) were refluxedin toluene (5 ml) overnight. The solvent was evaporated and the residuewas filtered over silica gel with dichloromethane/methanol (20:1) aseluant to give the crude 4- and 5-substituted triazoles in 1:1 ratio.This mixture was dissolved in tetrahydrofuran/methanol (2:1, 20 ml),acetic acid was added (5 drops) and it was hydrogenated over Pd/C (10%)at normal pressure and room temperature for two days. It was filteredthrough a 0.45 μM membrane and solvent was removed under vacuum.Chromatography on silica gel with dichloromethane/methanol (20:1) gave176 mg (19%) of the title compound as a colourless solid.

MS (ESP): 425.12 (MH⁺) for C₁₈H₂₁FN₄O₅S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.06 (m, 2H); 2.17 (m, 2H); 3.12 (m, 2H); 3.22 (m, 1H); 3.39 (m, 2H);3.89 (dd, 1H); 4.25 (dd, 1H); 4.53 (d, 2H); 4.80 (d, 2H); 5.14 (m, 1H);5.23 (dd, 1H); 5.84 (m, 1H); 7.26 (dd, 1H); 7.39 (dd, 1H); 7.45 (dd,1H); 8.03 (s, 1H). 4-Substitution on the triazole moiety was confirmedby NOE studies.

EXAMPLE 19(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(1H-1,2,3-triazol-4-ylthiomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-bromomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 10) (211 mg, 0.44 mmol) and 1H-1,2,3-triazole-4-thiol, sodiumsalt, (80 mg, 0.65 mmol) were dissolved in DMF (2 ml) and left overnightat room temperature. DMF was removed under vacuum. Chromatography onsilica gel with dichloromethane/methanol (15:1) gave 170 mg (77%) of thetitle compound as a colourless solid.

MS (ESP): 505.92 (MH⁺) for C₂₀H₂₀FN₇O₄S₂ ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.97 (m, 2H); 3.30–3.45 (m, 2H, under HDO); 3.74 (s, 2H); 3.87–3.93 (m,3H); 4.22–4.27 (m, 3H); 4.79 (d, 2H); 5.13 (m, 1H); 5.83 (m, 1H); 7.29(dd, 1H); 7.40 (dd, 1H); 7.47 (dd, 1H); 7.88 (s, 1H); 8.00 (s, 1H).

EXAMPLE 20(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(1H-imidazol-2-ylthio)methyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(diphenoxyphosphinyl)oxymethyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 15) (0.125 g, 0.19 mmol) was added to a solution of2-mercaptoimidazole (38 mg, 0.38 mmol) in DMF (2 ml) and the resultingsolution was added to a suspension of sodium hydride (15 mg, 0.38 mmol)in DMF (2 ml). The reaction mixture was stirred for 30 minutes and thenquenched with excess of aqueous sodium bicarbonate. The mixture wasextracted with ethyl acetate, was washed with sodium bicarbonate, waterand brine, dried over sodium sulfate and concentrated in vacuo to give40 mg (42%) of the title compound as a colourless solid.

MS (ESP): 505.10 (MH⁺) for C₂₁H₂₁FN₆O₄S₂ ¹H-NMR(DMSO-d₆) δ: 12.12 (brs,1H); 7.91 (s, 1H); 7.48 (m, 2H); 7.29 (m, 1H); 7.05 (brs, 2H); 5.77 (s,1H); 5.10 (m, 1H); 4.77 (d, 2H); 4.29 (s, 2H); 4.24 (dd, 1H); 3.87 (m,3H); 3.3 (m, 2H); 2.95 (s, 2H).

EXAMPLE 21(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(phenylmethyl)thiomethyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

Sodium hydride (30 mg, 0.76 mmol) was suspended in DMF (10 ml),thiophenol (0.09 ml, 0.76 mmol) was added, followed by addition of(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(diphenoxyphosphinyl)oxymethyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 15) (250 mg, 0.38 mmol). The reaction mixture was stirred for 5hours, then quenched with sodium bicarbonate solution, diluted withethyl acetate, washed with water and brine, dried over sodium sulfateand concentrated in vacuo. Chromatography on silica gel with 2.5%methanol in dichloromethane gave the title compound as an off-whitesolid (29 mg).

MS (ESP): 529.08 (M+H⁺) for C₂₅H₂₅FN₄O₄S₂ ¹H-NMR(CDCl₃) δ: 7.60 (s, 1H);7.23 (m, 8H); 5.74 (m, 1H); 5.05 (m, 1H); 4.73 (d, 2H); 4.17 (t, 1H);4.02 (m, 1H); 3.80 (s, 2H); 3.66 (m, 4H) 3.24 (m, 2H); 3.07 (m, 2H).

EXAMPLE 22(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(dimethylamino)methyl-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-bromomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 10) (250 mg, 0.52 mmol) was dissolved in DMF (1.5 ml) anddimethylamine (in water, 40%, 250 μl, 2.2 mmol) was added. The mixturewas heated to 50° C. for 30 minutes. Triethylamine (1 ml) was added andsolvent was removed under vacuum. Chromatography on silica gel withacetonitrile/water (5:1 to 3:1) gave 90 mg (39%) of the title compoundas a colourless solid.

MS (ESP): 450.27 (MH⁺) for C₂₀H₂₄FN₅O₄S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.09 (s, 6H); 2.96 (m, 2H); 3.30–3.39 (m, 2H); 3.48 (s, 2H); 3.90–3.93(m, 3H); 4.26 (dd, 1H); 4.78–4.85 (m, 2H); 5.17 (m, 1H); 5.83 (m, 1H);7.27 (dd, 1H); 7.39 (dd, 1H); 7.44 (dd, 1H); 8.02 (s, 1H).

EXAMPLE 23(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-carboxaldehyde-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

Oxalylchloride (1.36 ml, 15.6 mmol) in dichloromethane (30 ml) wascooled to −50° C. DMSO (1.42 mL, 20 mmol) in dichloromethane (30 ml) wasadded drop wise under stirring. The reaction mixture was stirred for 10minutes and(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 9) (5 g, 11.8 mmol), (dissolved in N-methylpyrrolidone (25 ml)and then diluted with dichloromethane (25 ml)) was added drop wise andthe resulting mixture vigorously stirred for 1 hour.N,N-Diisopropylethylamine (10 ml, 57.4 mmol) was added dropwise, thereaction mixture was warmed to −40° C. and then stirred for anotherhour. The reaction mixture was then slowly allowed to warm to −20° C.and held at this temperature over night. The homogeneous solution wasdirectly applied onto a silica gel column and eluted withhexanes/acetone (1:1 to 1:2). Fractions containing product were pooledand concentrated under vacuum. The product was then precipitated fromacetone (100 ml) by the addition of hexanes (700 ml) to give 4.2 g (84%)of the title compound as a colourless solid.

MS (ESP): 419.29 (M−H⁻) for C₁₈H₁₇FN₄O₅S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.98 (m, 2H); 3.29–3.38 (m, 2H); 3.93 (s, 2H); 3.97 (dd, 1H); 4.29 (dd,1H); 4.94 (d, 2H); 5.22 (m, 1H); 5.84 (m, 1H); 7.32 (dd, 1H); 7.42 (dd,1H); 7.48 (dd, 1H); 8.95 (s, 1H); 10.05 (s, 1H).

EXAMPLE 24(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-difluoromethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-carboxaldehyde-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 23) (100 mg, 0.24 mmol) was dissolved/suspended indichloromethane (10 ml). [Bis(2-methoxyethyl)amino]sulfur trifluoride(71 μl, 0.39 mmol) and a catalytic amount of ethanol (1.3 μl) were addedand the mixture was refluxed under stirring for 36 hours. The reactionmixture was loaded onto a silica gel column and eluted withhexanes/acetone (−1.25:1) to give 38 mg (36%) of the title compound as acolourless solid.

MS (ESP): 443 (MH⁺) for C₁₈H₁₇F₃N₄O₄S ¹H-NMR (DMSO-d₆) (300 MHz) δ: 2.98(m, 2H); 3.31–3.37 (m, 2H); 3.93 (brs, 2H); 3.94 (dd, 1H); 4.29 (dd,1H); 4.91 (d, 2H); 5.20 (m, 1H); 5.84 (m, 1H); 7.25 (dd, 1H); 7.31 (dd,1H); 7.41 (dd, 1H); 7.47 (dd, 1H); 8.61 (m, 1H).

EXAMPLE 25(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-carboxaldehyde-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 23) (5 g, 11.9 mmol) and carbon tetrabromide (4.34 g, 13.1mmol) were dissolved/suspended in dichloromethane (100 ml) and it wascooled to 0° C. Triphenylphosphine (6.55 g, 25 mmol) was added and itwas stirred for 30 minutes at 0° C. and then for 1 hour at roomtemperature. The reaction mixture was applied onto a silica gel columnand it was eluted with toluene/ethanol (10:1 to 7:1) to give 6.1 g (89%)of the title compound as an off-white solid.

MS (ESP): 575, 577, 579 (MH⁺) for C₁₉H₁₇Br₂FN₄O₄S ¹H-NMR (DMSO-d₆) (500MHz) δ: 2.98 (m, 2H); 3.31–3.40 (m, 2H); 3.93–3.96 (m, 3H); 4.28 (dd,1H); 4.90 (d, 2H); 5.21 (m, 1H); 5.85 (m, 1H); 7.31 (dd, 1H); 7.42 (dd,1H); 7.47 (dd, 1H); 7.80 (s, 1H); 8.68 (s, 1H).

EXAMPLE 26(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fuorophenyl]-5-[4-(2-(3-methyl-5-isoxazolyl)ethynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 25) (0.6 g, 1.04 mmol), 3-methyl-5-(tributylstannyl)-isoxazole(407 mg, 1.09 mmol) [Sakamoto, T. et al., Condensed Heteroaromatic RingSystems. XIX. Synthesis and Reactions of 5-(Tributylstannyl)isoxazoles.Tetrahedron, 47, 28, 5111–5118] and tris(2-furyl)phosphine (37 mg, 0.16mmol) were dissolved in DMF (2.5 ml). Diisopropylethyl amine (0.272 ml,1.56 mmol) was added, the reaction mixture was flushed with argon andtris (dibenzylideneacetone)dipalladium (0) (30 mg, 0.03 mmol) was added.The mixture was heated to 85° C. for 20 hours under argon. The solventwas removed under vacuum. Chromatography on silica gel withdichloromethane/DMF (30:1) gave 30 mg (6%) of the title compound as acolourless solid.

MS (ESP): 497.91 (MH⁺) for C₂₃H₂₀FN₅O₅S ¹H-NMR (DMSO-d₆) (300 MHz) δ:2.30 (s, 3H); 2.95 (m, 2H); 3.30–3.44 (m, 2H); 3.88–3.97 (m, 3H); 4.27(dd, 1H); 4.90 (d, 2H); 5.19 (m, 1H); 5.82 (m, 1H); 6.94 (s, 1H); 7.29(dd, 1H); 7.40 (dd, 1H); 7.45 (dd, 1H); 8.78 (s, 1H).

EXAMPLE 27(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-(3-buten-1-ynyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 25) (0.3 g, 0.52 mmol), allyl tributyl tin (160 μl, 0.55 mmol)and tris(4-methoxyphenyl)phosphine (28 mg, 0.08 mmol) were dissolved inDMF (2.5 ml). Diisopropylethyl amine (136 μl, 0.78 mmol) was added, thereaction mixture was flushed with argon andtris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) was added.The mixture was heated to 80° C. for 10 hours under argon. It wasdiluted with ethyl acetate, washed with phosphate buffer (pH 7),saturated aqueous potassium fluoride solution and with water and driedover sodium sulfate. Chromatography on silica gel withchloroform/methanol (15:1) gave 32 mg (14%) of the title compound as acolourless solid.

MS (ESP): 442.97 (MH⁺) for C₂₁H₁₉FN₄O₄S ¹H-NMR (DMSO-d₆) (300 MHz) δ:2.95 (m, 2H); 3.29–3.43 (m, 2H); 3.89–3.95 (m, 3H); 4.25 (dd, 1H); 4.84(d, 2H); 5.17 (m, 1H); 5.70 (dd, 1H); 5.80 (dd, 1H); 5.82 (m, 1H); 6.16(dd, 1H); 7.29 (dd, 1H); 7.40 (dd, 1H); 7.45 (dd, 1H); 8.50 (s, 1H).

EXAMPLE 28(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-((E)-2-bromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(0.4 g, 0.69 mmol) was dissolved/supended in ethanol (2 ml) anddiethylphosphite (0.36 ml, 2.79 mmol). Triethylamine (0.195 ml, 1.39mmol) was added and the reaction mixture heated under vigorous stirringat 90° C. for 5 hours. It was cooled to room temperature, diluted withdichloromethane, washed with phosphate buffer (pH 7) and dried oversodium sulfate. Chromatography on silica gel with dichloromethane/DMF(50:1 to 40:1) gave 151 mg (44%) of the title compound as a colourlesssolid.

MS (ESP): 537.7/539.9 (MH⁺+41 (acetonitrile)) for C₁₉H₁₈BrFN₄O₄S ¹H-NMR(CD₃CN) (500 MHz) δ: 3.04 (m, 2H); 3.23–3.28 (m, 2H); 3.81 (brs, 2H);3.87 (dd, 1H); 4.22 (dd, 1H); 4.72 (dd, 1H); 4.78 (dd, 1H); 5.10 (m,1H); 5.82 (m, 1H); 7.09 (d, 1H); 7.15 (d, 1H); 7.20 (dd, 1H); 7.33 (dd,1H); 7.37 (dd, 1H); 7.97 (s, 1H).

EXAMPLE 29(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2-bromoethynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 25) (0.5 g, 0.87 mmol) was dissolved in DMSO (87 ml) and cooledto 15° C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.262 ml, 1.75mmol), dissolved in DMSO (1.7 ml), was added drop wise under stirringover 30 minutes. The temperature was maintained at 15–18° C. and after 6hours more DBU (0.125 ml, 0.83 mmol) was added drop wise via a syringeand the resulting solution stirred for another 30 minutes. The reactionwas quenched with cold aqueous HCl (0.5 M), extracted withdichloromethane, washed with water and dried over sodium sulfate.Chromatography on silica gel with hexanes/acetone (1.5:1 to 1:1) gave108 mg (25%) of the title product as a colourless solid.

MS (APCI, Pos.): 495/497 (MH⁺) for C₁₉H₁₆BrFN₄O₄S ¹H-NMR (DMSO-d₆) (500MHz) δ: 2.97 (m, 2H); 3.33–3.40 (m, 2H); 3.90–3.95 (m, 3H); 4.26 (dd,1H); 4.86 (d, 2H); 5.17 (m, 1H); 5.84 (m, 1H); 6.16 (dd, 1H); 7.31 (dd,1H); 7.41 (dd, 1H); 7.46 (dd, 1H); 8.55 (s, 1H).

EXAMPLE 30(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2-(ethylmethylamino)-2-oxoethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 25) (0.25 g, 0.43 mmol) was dissolved in DMF (1.5 ml).Ethylmethylamine (0.186 ml, 2.16 mmol) and water (0.5 ml) were added andthe reaction mixture was heated for 2 hours to 90° C. Moreethylmethylamine (0.2 ml, 2.33 mmol) was added and it was heated foranother 1.5 hours. The reaction mixture was cooled to room temperatureand the solvent was removed under vacuum. Chromatography on silica gelwith toluene/ethanol (5:1) and then with hexanes/acetone (1:2) gave 27mg (13%) of the title compound as a colourless solid.

MS (ESP): 492.34 (MH⁺) for C₂₂H₂₆FN₅O₅S ¹H-NMR (DMSO-d₆) (500 MHz) δ:1.01 and 1.08 (2×dd, 3H); 2.81 and 3.00 (2×s, 3H); 2.97 (m, 2H);3.29–3.45 (m, 4H); 3.75 and 3.77 (2×s, 2H); 3.89–3.93 (m, 3H); 4.26 (dd,1H); 4.81 (d, 2H); 5.16 (m, 1H); 5.83 (m, 1H); 7.30 (dd, 1H); 7.41 (dd,1H); 7.47 (dd, 1H); 7.99 and 8.01 (2×s, 1H).

EXAMPLE 31(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-(2-(dimethylamino)-2-oxoethyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2,2-dibromoethenyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 25) (0.25 g, 0.43 mmol) was dissolved in DMF (1.5 ml).Dimethylamine (0.250 ml, 40% in water, 2.2 mmol) and water (0.25 ml)were added and the reaction mixture was heated for 3 hours to 90° C. Itwas cooled to room temperature and the solvent was removed under vacuum.Chromatography on silica gel with dichloromethane/methanol (20:1) gave74 mg (36%) of the title compound as a colourless solid.

MS (ESP): 478.29 (MH⁺) for C₂₁H₂₄FN₅O₅S ¹H-NMR (DMSO-D₆) (500 MHz) δ:2.84 (s, 3H); 2.97 (m, 2H); 3.03 (s, 3H); 3.29–3.43 (m, 2H); 3.77 (s,2H); 3.89–3.93 (m, 3H); 4.26 (dd, 1H); 4.81 (d, 2H); 5.16 (m, 1H); 5.84(m, 1H); 7.30 (dd, 1H); 7.41 (dd, 1H); 7.48 (dd, 1H); 8.00 (s, 1H).

EXAMPLE 32(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(ethylaminocarbonyloxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 9) (150 mg, 0.36 mmol) was dissolved in pyridine (2 ml),ethylisocyanate (234 mg, 3.6 mmol) was added and the resulting mixturewas stirred for 4 hours at 90° C. It was cooled to room temperature, thesolvent was removed under vacuum and the residue was purified by flashchromatography on silica gel with 5% of methanol in dichloromethane togive the title product (170 mg).

MS (ESP): 494.21 (MH⁺) for C₂₁H₂₄FN₅O₆S ¹H-NMR(DMSO-d₆) δ: 1.00 (t, 3H);2.96 (m, 2H); 3.00 (m, 2H); 3.34 (m, 2H); 3.91 (m, 3H); 4.25 (dd, 1H);4.83 (d, 2H); 5.04 (s, 2H); 5.14 (m, 1H); 5.82 (m, 1H); 7.18 (m, 1H);7.27 (m, 1H); 7.40 (m, 1H); 7.48 (m, 1H); 8.16 (s, 1H).

EXAMPLE 33(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-amino)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

A mixture of(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-carboxy)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Reference Example 3) (873 mg, 2.0 mmol), triethylamine (222 mg, 2.2mmol) and t-butanol (10 ml) were heated to 70° C. with vigrous stirring.Diphenylphosphoryl azide (608 mg, 2.2 mmol) was added drop wise and theresulting mixture was refluxed for 12 hours. The solvent was evaporated,the residue was dissolved in dichloromethane (6 ml) and methanol (0.5ml), hexane (20 ml) was added and the resulting precipitate was filteredto give a white solid (900 mg). This product (160 mg) was stirred in amixture of dry dichloromethane (3 ml) and trifluoroacetic acid (3 ml)for 1 hour at room temperature. The solvent and excess oftrifluoroacetic acid were removed under vacuum and the residue waspurified by reverse phase chromatography with 5%˜95% acetonitrile inwater (containing 0.1% TFA) to give the title product (70 mg).

MS (ESP): 408.21 (MH⁺) for C₁₇H₁₈FN₅O₄S ¹H-NMR(DMSO-d₆) δ: 2.96 (m, 2H);3.43 (m, 2H); 3.90 (m, 3H); 4.23 (dd, 1H); 4.68 (d, 2H); 5.12 (m, 1H);5.77 (m, 1H); 7.27 (m, 1H); 7.38 (m, 1H); 7.45 (m, 1H); 7.62 (s, 1H);(NH₂ not observed due to exchange).

The intermediate for this example was prepared as follows:

Intermediate 3(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-carboxy)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one(6.9 g, 18.83 mmol) (Reference Example 2) was dissolved in dry1,4-dioxane (15 ml), 2-propynoic acid t-butylester (4.75 g, 37.67 mmol)was added and the resulting mixture was refluxed for 12 hours undervigorous stirring. Ethyl acetate (30 ml) was added and the resultingprecipitate was filtered, washed with ethyl acetate and dried as a whitesolid (5 g). This solid was suspended in dichloromethane (16 ml),followed by drop wise addition of trifluoroacetic acid (8 ml) and theresulting mixture was stirred over night. The solvent was removed undervacuum and the residue was purified by precipitation fromdichloromethane to give the title product as an off-white solid (3.3 g).

MS (ESP): 435.25 (M−H⁻) for C₁₈H₁₇FN₄O₆S ¹H-NMR(DMSO-d₆) δ: 2.89 (m,2H); 3.31 (m, 2H); 3.84 (m, 2H); 3.88 (m, 1H); 4.19 (dd, 1H); 4.80 (d,2H); 5.12 (m, 1H); 5.75 (m, 1H); 7.22 (m, 1H); 7.32 (m, 1H); 7.40 (m,1H); 8.66 (s, 1H); 13.11 (br, 1H).

EXAMPLE 34(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-acetylamino)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-amino)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 33) (23 mg, 0.057 mmol) was dissolved inpyridine/dichloromethane (1:1, 5 ml). Acetyl chloride (22 mg, 5 eq.) wasadded and the resulting mixture was stirred at room temperature for 24hours. The solvent was removed under vaccum and the residure waspurified by flash chromatography on silica gel with 5% methanol indichloromethane to give the title product (25 mg).

MS (ESP): 450.27 (MH⁺) for C₁₉H₂₀FN₅O₅S ¹H-NMR(DMSO-d₆) δ: 2.04 (s, 3H);2.96 (m, 2H); 3.43 (m, 2H); 3.90 (m, 3H); 4.23 (dd, 1H); 4.73 (d, 2H);5.12 (m, 1H); 5.77 (m, 1H); 7.27 (m, 1H); 7.38 (m, 1H); 7.45 (m, 1H);8.20 (s, 1H); 10.89 (s, 1H).

EXAMPLE 35(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-ethoxy)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one(Reference Example 2) (733 mg, 2.0 mmol) was dissolved in dryacetonitrile (8 ml). Ethoxyacetylene (420 mg, 6.0 mmol), 2,6-lutidine(236 mg, 2.2 mmol) and copper iodide (38 mg, 10 mmol %) were added andthe resulting mixture was stirred at room temperature for 12 hours.Water was added and the mixture was extracted with dichloromethane(3×100 ml). The combined organic layers were concentrated under vacuumand the residue was purified by flash chromatography on silica gel with5% of methanol in dichloromethane to give the title product (666 mg).

MS (ESP): 437.25 (MH⁺) for C₁₉H₂₁FN₄O₅S ¹H-NMR(DMSO-d₆) δ: 1.30 (t, 3H);2.97 (m, 2H); 3.34 (m, 2H); 3.91 (m, 3H); 4.28 (q, 2H); 4.26 (dd, 1H);4.71 (d, 2H); 5.15 (m, 1H); 5.83 (m, 1H); 7.30 (m, 1H); 7.42 (m, 1H);7.47 (m, 1H); 7.70 (s, 1H).

EXAMPLE 36(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-bromo)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (Reference Example 2) (1.5 g, 4.1 mmol) and1-bromo-1-ethenesulfonyl chloride (1.8 g, 8.8 mmol) were heated to 90°C. for one hour with stirring. The reaction mixture was cooled to roomtemperature, diluted with dichloromethane (10 ml) and applied onto asilica gel column. Elution with hexanes/acetone (2:1 to 1:1) gave 1.46 g(76%) of the title compound as a colourless solid.

MS (ESP): 471/473 (MH⁺) for C₁₇H₁₆BrFN₄O₄S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.98 (m, 2H); 3.34–3.38 (m, 2H); 3.92–3.96 (m, 3H); 4.27 (dd, 1H, J 9.2,9.2 Hz); 4.87 (d, 2H, J 5.2 Hz); 5.18 (m, 1H); 5.84 (m, 1H); 7.31 (dd,1H, J 2.2, 8.6 Hz); 7.42 (dd, 1H, J 8.6, 8.8 Hz); 7.47 (dd, 1H, J 2.2,13.7 Hz); 8.49 (s, 1H).

EXAMPLE 37(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-chloro-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one(Reference Example 2) (1.0 g, 2.7 mmol) and 1-chloro-1-ethenesulfonylchloride (Intermediate 4) (1.1 g, 6.8 mmol) were heated to 90° C. forone hour with stirring. The reaction mixture was cooled to roomtemperature, diluted with dichloromethane (10 ml) and applied onto asilica gel column. Elution with hexanes/acetone (1.5:1) gave 0.745 g(64%) of the title compound as a colourless solid.

MS (ESP): 427 (MH⁺) for C₁₇H₁₆ClFN₄O₄S ¹H-NMR (DMSO-d₆) (300 MHz) δ:2.96 (m, 2H); 3.29–3.43 (m, 2H); 3.90–3.95 (m, 3H); 4.25 (dd, 1H); 4.83(d, 2H); 5.16 (m, 1H); 5.82 (m, 1H); 7.29 (dd, 1H); 7.40 (dd, 1H); 7.45(dd, 1H); 8.45 (s, 1H).

Intermediate 4 1-Chloro-1-ethene sulfonyl chloride

A stirred solution of 1,2-dichloroethanesulfonyl chloride (14.54 g,73.62 mmol) (Gladschtein et al., Zh.Obshch.Khim.; 28; 1958; 2107, 2110;Engl. Ed. p. 2145,2146,2148) in dry ether (140 ml) was treated at −60°C. to −50° C. under an atmosphere of nitrogen with 2,6-lutidine (10.30ml, 88.34 mmol). The stirred reaction mixture was allowed to warm toroom temperature, cooled to 0° C. and then treated slowly with diluteaqueous sulfuric acid (1%; 50 ml). The ether phase was separated, washedwith dilute aqueous sulfuric acid (1%; 2×60 ml) and brine (3×60 ml),dried over magnesium sulfate, and concentrated under reduced pressure(60 mmHg) to give an oil that was purified by distillation to give1-chloro-1-ethenesulfonyl chloride (7.2 g, 61%), b.p. 26° C./2 mmHg.

¹H-NMR (CDCl₃) δ 6.70 (d, J=3.8 Hz, 1H) and 6.22 (d, J=3.8 Hz, 1H).

EXAMPLE 38 (5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran4-yl)-3-fluorophenyl]-5-[4-fluoro-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)-oxazolidin-2-one(Reference Example 2) (0.7 g, 1.9 mmol) and(1-fluoroethenyl)-phenylsulfane dioxide (0.7 g, 3.8 mmol) (D. P. Mathewsand J. R. McCarthy, JOC 55 (9), 1990, p 2973) were suspended/dissolvedin toluene (5 ml) and heated to reflux under stirring for 2 days. Thereaction mixture was cooled to room temperature, diluted withdichloromethane, washed with phosphate buffer (pH 7) and dried oversodium sulfate. Chromatography on silica gel with hexanes/acetone (1:1)gave 28 mg (4%) of the title compound as a colourless solid (Rf ˜0.25,TLC:hexanes/acetone, 1:1). The major product was the corresponding5-fluoro-1,2,3-triazoyl compound with an Rf of ˜0.2.

MS (ESP): 409.19 (M−H⁻) for C₁₇H₁₆F₂N₄O₄S ¹H-NMR (DMSO-d₆) (500 MHz) δ:2.98 (m, 2H); 3.32–3.39 (m, 2H); 3.91–3.95 (m, 3H); 4.27 (dd, 1H); 4.81(d, 2H); 5.17 (m, 1H); 5.84 (m, 1H); 7.32 (dd, 1H); 7.42 (dd, 1H); 7.48(dd, 1H); 8.22 (d, 1H).

EXAMPLE 39(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(3-hydroxy-1-propynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-bromo-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 36) (235 mg, 0.5 mmol), propargyl alcohol (42 mg, 0.75 mmol),tetrakis(triphenylphosphine)palladium (0) (29 mg, 5 mol %) and copperiodide (5 mg, 5 mol %) were mixed in N-methylpyrrolidone/triethylamine(5 ml, 5:1). The reaction mixture was flushed with nitrogen and heatedto 90° C. for 48 hours. The reaction mixture was filtered and extractedwith ethyl acetate/water, the organic phase was concentrated andpurified by flash chromatography on silica gel with 5% of methanol indichloromethane to give the title product (27 mg).

MS (ESP): 447.27 (MH⁺) for C₂₀H₁₉FN₄O₅S ¹H-NMR(DMSO-d₆) δ: 2.96 (m, 2H);3.34 (m, 2H); 3.93 (m, 2H); 3.93 (m, 1H); 4.22 (dd, 1H); 4.27 (d, 2H);4.82 (d, 2H); 5.18 (m, 1H); 5.37 (t, 1H); 5.75 (s, 1H); 5.81 (m, 1H);7.25 (m, 1H); 7.38 (m, 1H); 7.42 (m, 1H); 8.47 (s, 1H).

EXAMPLE 40(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-(2-propynyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(3-(trimethylsilyl)-2-propynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(251 mg, 0.5 mmol) (Intermediate 5) was dissolved in methanol (10 ml).Potassium hydroxide (1 M, 0.75 ml) was added and the mixture was stirredat room temperature for 4 hours. Aqueous HCl (2M, 0.5 ml) was added, theexcess of methanol was evaporated and the residue was extracted withdichloromethane, dried over magnesium sulfate and concentrated to givethe title product (220 mg).

MS (ESP): 430.95 (MH⁺) for C₂₀H₁₉FN₄O₄S ¹H-NMR(DMSO-d₆) δ: 2.96 (m, 2H);3.34 (m, 2H); 3.72 (s, 2H); 3.92, (m, 3H); 4.22 (dd, 1H); 4.38 (s, 1H);4.82 (d, 2H); 5.18 (m, 1H); 5.81 (m, 1H); 7.22 (m, 1H); 7.38 (m, 1H);7.42 (m, 1H); 8.01 (s, 1H).

The intermediate for this compound was prepared as follows:

Intermediate 55(R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(3-(trimethylsilyl)-2-propynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one(Reference Example 2) (620 mg, 1.69 mmol) was reacted with1-trimethylsilyl-1,4-pentadiyne (461 mg, 3.38 mmol), 2,6-lutidine (199mg, 3.38 mmol) and copper iodide (10 mmol %) as described for Example35. Flash chromatography on silica gel with 2.5% of methanol indichloromethane gave the title product as a white solid (525 mg).

MS (ESP): 502.98 (MH⁺) for C₂₃H₂₇FN₄O₄SSi ¹H-NMR(DMSO-d₆) δ: 0.00 (s,9H); 2.96 (m, 2H); 3.34 (m, 2H); 3.68 (s, 2H); 3.91 (m, 3H); 4.28 (dd,1H); 4.85 (m, 2H); 5.19 (m, 1H); 5.81 (m, 1H); 7.26 (m, 1H); 7.38 (m,1H); 7.43 (m, 1H); 8.01 (s, 1H).

EXAMPLE 415(R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(4-dimethylamino-2-butynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(prop-2-ynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 40) (150 mg, 0.35 mmol) was mixed with formaldehyde (57 mg, 0.7mmol) in acetonitrile (10 ml), copper iodide (3.5 mg, 10 mmol %) wasadded, followed by the addition of dimethylamine (32 mg, 0.7 mmol) andthe resulting mixture was stirred at 80° C. for 12 hours. The solventwas removed under vacuum and the residue was purified by reverse phasechromatography with 15%–95% acetonitrile in water (containing 0.1% TFA)to give the title product as a TFA salt (85 mg).

MS (ESP): 516.94 (MH⁺) for C₂₃H₂₆FN₅O₄S ¹H-NMR(DMSO-d₆)(TFA salt) δ:2.72 (s, 6H); 2.96 (m, 2H); 3.36 (m, 2H); 3.72 (s, 2H); 3.92 (m, 3H);4.05 (s, 2H); 4.22 (dd, 1H); 4.78 (d, 2H); 5.18 (m, 1H); 5.81 (m, 1H);7.22 (m, 1H); 7.38 (m, 1H); 7.42 (m, 1H); 8.05 (s, 1H); 9.95 (brs, 1H).

EXAMPLE 425(R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(4-diethylamino-2-butynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2-propynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 40) (150 mg, 0.35 mmol) was reacted with diethylamine (51 mg,0.7 mmol) as described for Example 41 to give 125 mg of the titlecompound.

MS (ESP): 516.94 (MH⁺) for C₂₅H₃₀FN₅O₄S ¹H-NMR(DMSO-d₆)(TFA salt) δ:1.15 (t, 6H); 2.96 (m, 2H); 3.18 (m, 4H); 3.36 (m, 2H); 3.72 (s, 2H);3.92 (m, 2H); 3.92 (m, 1H); 4.10 (s, 2H); 4.22 (dd, 1H); 4.78 (d, 2H);5.18 (m, 1H); 5.81 (m, 1H); 7.22 (m, 1H); 7.38 (m, 1H); 7.42 (m, 1H);8.05 (s, 1H); 9.85 (brs, 1H).

EXAMPLE 435(R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl-3-fluorophenyl]-5-[4-(4-(2,5-dihydro-1H-pyrrol-1-yl)-2-butynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2-propynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 40) (150 mg, 0.35 mmol) was reacted with 3-pyrroline (48.4 mg,0.7 mmol) as described for Example 41 to give 50 mg of the titlecompound.

MS (ESP): 511.93 (MH⁺) for C₂₅H₂₆FN₅O₄S ¹H-NMR(DMSO-d₆) δ: 2.96 (m, 2H);3.31 (t, 2H); 3.36 (m, 2H); 3.92 (m, 3H); 4.22 (dd, 1H); 4.45 (d, 2H);4.78 (d, 2H); 5.18 (m, 1H); 5.65 (m, 2H); 5.81 (m, 1H); 5.92 (d, 2H);6.68 (d, 2H); 7.22 (m, 1H); 7.38 (m, 1H); 7.42 (m, 1H); 8.01 (s, 1H).

EXAMPLE 445(R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-(4-(morpholinyl)-2-butynyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2-propynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 40) (150 mg, 0.35 mmol) was reacted with morpholine (61 mg, 0.7mmol) as described for Example 41 to give 175 mg of the title compound.

MS (ESP): 530.89 (MH⁺) for C₂₅H₂₈FN₅O₅S ¹H-NMR(pyridine-d₅)(TFA salt) δ:3.66 (t, 4H); 4.26 (m, 2H); 4.43 (d, 2H); 4.57 (m, 2H); 4.84 (t, 4H);5.04 (s, 2H); 5.19 (m, 2H); 5.25 (m, 1H); 5.40 (dd, 1H); 6.15 (m, 2H);6.46 (m, 1H); 6.95 (m, 1H); 8.34 (m, 1H); 8.44 (m, 1H); 8.69 (s, 1H);8.82 (m, 1H); 9.32 (s, 1H).

EXAMPLE 45(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-ethynyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-((2-trimethylsilyl)ethynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Intermediate 6) (11.5 g, 23.5 mmol) was dissolved in methanol (100 ml),potasium hydroxide (1 M, 36 ml) was added and the mixture was stirred atroom temperature for 4 hours. Aqueous HCl (2M, 24 ml) was added, theexcess of methanol was evaporated and the residue was extracted withdichloromethane. The organic phase was collected and concentrated, theresidue was dissolved in a mixture of 10% methanol in dichloromethane,followed by addition of hexane and the resulting precipitate wascollected by filtration to give the title product (8.8 g).

MS (ESP): 417.24 (MH⁺) for C₁₉H₁₇FN₄O₄S ¹H-NMR(DMSO-d₆) δ: 2.96 (m, 2H);3.34 (m, 2H); 3.92 (m, 3H); 4.22 (dd, 1H); 4.38 (s, 1H); 4.82 (d, 2H);5.18 (m, 1H); 5.81 (m, 1H); 7.22 (m, 1H); 7.38 (m, 1H) 7.42 (m, 1H);8.51 (s, 1H).

The intermediate for this compound was prepared as follows:

Intermediate 6(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-((2-trimethylsilyl)ethynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)-oxazolidin-2-one(Reference Example 2) (11 g, 30 mmol) was dissolved in dry acetonitrile,buta-1,3-diynyl(trimethyl)silane (5.8 g, 47.5 mmol), 2,6-lutidine (3.53g, 33 mmol) and copper iodide (571 mg, 10 mmol %) were added and theresulting mixture was stirred at room temperature for 12 hours. Themixture was then poured into water (250 ml) and was stirred for 10minutes. The formed precipitate was filtered, washed with water anddiethyl ether (3×50 ml). The solid was collected and dried under highvaccum to give the title product (11.8 g).

MS (ESP): 489.24 (MH⁺) for C₂₂H₂₅FN₄O₄SSi ¹H-NMR(DMSO-d₆) δ: 0.01 (s,9H); 2.96 (m, 2H); 3.34 (m, 2H); 3.91 (m, 3H); 4.28 (dd, 1H); 4.85 (m,2H); 5.20 (m, 1H); 5.81 (m, 1H); 7.26 (m, 1H); 7.38 (m, 1H); 7.43 (m,1H); 8.51 (s, 1H).

EXAMPLE 46(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-hydroxy-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-ethoxy-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 35) (390 mg, 0.89 mmol) was dissolved in dry dichloromethane (5ml), cooled down to 0° C., boron tribromide was added via syringe, thenthe mixture was warmed up to 45° C. and stirred for 48 hours. It wasquenched dropwise with water (10 ml) and was extracted withdichloromethane. The combined organic layer was concentrated undervacuum and the residue was purified by reverse phase chromatography with5%–95% acetonitrile in water (containing 0.1% TFA) to give the titleproduct (221 mg).

MS (ESP): 408.92 (MH⁺) for C₁₇H₁₇FN₄O₅S ¹H-NMR(DMSO-d₆) δ: 2.92 (m, 2H);3.34 (m, 2H); 3.91 (m, 1H); 3.92 (m, 2H); 4.22 (dd, 1H); 4.70 (d, 2H);5.14 (m, 1H); 5.81 (m, 1H); 7.28 (m, 1H); 7.36 (m, 1H); 7.37 (s, 1H);7.44 (m, 1H); 10.01 (brs, 1H).

EXAMPLE 47(5R)-3-[3-Fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-5-[4-(fluoromethyl)-1H-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

Bis[(2-methoxyethyl)amino]sulfur trifluoride (150 μl, 0.81 mmol) wasadded to a solution of(5R)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-5-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-ylmethyl]-1,3-oxazolidin-2-one(Example 48) (222 mg, 0.60 mmol) in dichloromethane (2 ml) at −78° C.The reaction mixture was allowed to gradually warm to room temperature.After 20 hours, the reaction mixture was heated to 40° C. for 3 hoursbefore cooling to room temperature and quenching with methanol.Chromatography on silica gel with 7.5% methanol in dichloromethane gave36 mg of product.

MS (APCI): 375.0 (MH⁺) for C₁₇H₁₆F₂N₆O₂ ¹H-NMR (DMSO-d₆) δ: 2.15 (s,3H); 3.94 (dd, 1H); 4.29 (t, 1H); 4.86 (d, 2H); 5.17 (m, 1H); 5.38 (s,1H); 5.54 (s, 1H); 7.72 (s, 1H); 7.39 (dd, 1H); 7.61 (t, 1H); 7.66 (dd,1H); 7.86 (s, 1H); 8.37 (d, 1H).

EXAMPLE 48(5R)-3-[3-Fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-5-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

Propargyl alcohol (79 μl, 1.3 mmol), copper sulfate (37 μl of 0.30 Maqueous solution, 11 mmol), and sodium ascorbate (112 μl of 1.0 Maqueous solution, 0.11 mmol) were added to a solution of(5R)-5-(azidomethyl)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1,3-oxazolidin-2-one(Intermediate 7) (0.355 g, 1.12 mmol) in ethanol (2 ml) and water (2ml). The reaction mixture was allowed to stir at room temperature for 24h. The aqueous phase was extracted three times with dichloromethane, theorganic layers were combined and washed once with brine and dried overmagnesium sulfate. Chromatography on silica gel with 10% to 14% methanolin dichloromethane gave 0.197 g. of the title compound.

MS (APCI): 373.0 (MH⁺) for C₁₇H₁₇FN₆O₃

¹H-NMR (DMSO-d₆) δ: 2.15 (s, 3H); 3.92 (dd, 1H); 4.27 (t, 1H); 4.50 (d,2H); 4.80 (d, 2H); 5.15 (m, 1H); 5.20 (t, 1H); 7.22 (s, 1H); 7.39 (dd,1H); 7.61 (t, 1H); 7.67 (dd, 1H); 7.86 (s, 1H); 8.01 (s, 1H).

The intermediate for this example was prepared as follows:

Intermediate 7(5R)-5-(Azidomethyl)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]oxazolidin-2-one

Sodium azide (0.596 g, 9.08 mmol) and 18-crown-6 (0.025 g, 0.095 mmol)were added to a solution of(5R)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-ylmethylmethanesulfonate (WO 01/81350) (3.161 g, 8.56 mmol) in DMF (8.5 ml). Thereaction mixture was heated to 90° C. under an atmosphere of nitrogenfor 19 h. It was poured into a mixture of ethyl acetate and water andwas extracted three times with ethyl acetate. The combined organiclayers were washed once with brine, dried over sodium sulfate, filteredand the solvent was removed under vacuum to give 1.94 g of product as awhite solid.

MS (ESP): 317.13 (MH⁺) for C₁₄H₁₃FN₆O₂ ¹H-NMR (DMSO-d₆) δ: 2.16 (s, 3H);3.70 (dd, 1H); 3.78 (dd, 1H); 3.82 (dd, 1H); 4.18 (t, 1H); 4.92 (m, 1H);7.21 (s, 1H); 4.75 (dd, 1H); 7.62 (t, 1H); 7.73 (dd, 1H); 7.85 (s, 1H).

EXAMPLE 49(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5[(4-thiomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(3,6-Dihydro-1,1-dioxo-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[methylsulfonyloxymethyl]-2-oxazolidinone(WO 01/81350 A1) (2.0 g, 4.59 mmol) and 4-methylthio-1,2,3-triazole (458mg, 5.51 mmol) were dissolved in DMF (5 ml). Caesium carbonate (2.24 g,6.89 mmol) was added and the reaction mixture was stirred at roomtemperature for 12 hours. It was diluted with ethyl acetate (20 ml),washed with saturated aqueous ammonium chloride solution (10 ml), water(10 ml) and brine (10 ml) and dried over magnesium sulfate. The solventwas removed under vacuum and the crude product was purified by flashchromatograph on silica gel with 10% ethyl acetate in toluene to give 66mg of the title compound.

MS (ESP): 457.12 (MH⁺) for C₁₈H₁₈F₂N₄O₄S₂ ¹H-NMR(DMSO-d₆) δ: 2.52 (s,3H); 2.86 (m, 2H); 3.36 (m, 2H); 3.90 (m, 1H); 3.95 (m, 2H); 4.25 (dd,1H); 4.80 (d, 2H); 5.18 (m, 1H); 5.78 (s, 1H); 7.32 (d, 2H); 8.22 (s,1H).

The intermediate for this example:

(5R)-3-[4-(3,6-Dihydro-1,1-dioxido-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[methylsulfonyloxymethyl]oxazolidin-2-one

was prepared as described in WO 01/81350 A1 page 97.

EXAMPLE 50(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-cyclopropyl-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-azidomethyloxazolidin-2-one(WO 01/81350 A1) (450 mg, 1.17 mmol) and 1-ethynylcyclopropane (232 mg,3.51 mmol) were mixed in dry 1,4-dioxane (1.0 ml) in a microwavereaction tube. The resulting mixture was microwaved for 30 minutes at180° C. The solvent was removed under vacuum and the residue waspurified by flash chromatography on silica gel with 5% methanol indichloromethane to give the title product (552 mg) as a mixture of tworegio isomers (4-, 5-substituted triazole, ratio 1:1).

MS (ESP): 450.97 (MH⁺) for C₂₀H₂₀F₂N₄O₄S ¹H-NMR(DMSO-d₆) (for the4-substituted isomer) δ: 0.66 (m, 2H); 0.89 (m, 2H); 1.95 (m, 1H); 2.86(m, 2H); 3.37 (m, 2H); 3.89 (m, 1H); 3.95 (m, 2H); 4.24 (dd, 1H); 4.73(d, 2H); 5.14 (m, 1H); 5.78 (m, 1H); 7.31 (d, 2H); 7.88 (s, 1H).

EXAMPLE 51(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(2-hydroxyethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-azidomethyloxazolidin-2-one(WO 01/81350 A1) (2.31 g, 6.0 mmol) and 3-butyn-1-ol (1.26 g, 18 mmol)were reacted as described for Example 50. Flash chromatography on silicagel with 50% hexanes in acetone gave the title compound (800 mg) and thecorresponding 5-substituted regioisomer (700 mg).

MS (ESP): 455.11 (MH⁺) for C₁₉H₂₀F₂N₄O₅S ¹H-NMR(DMSO-d₆) δ: 2.77 (t,2H); 2.86 (m, 2H); 3.37 (m, 2H); 3.59 (q, 2H); 3.88 (m, 1H); 3.95 (m,2H); 4.25 (dd, 1H); 4.70 (t, 1H); 4.76 (d, 2H); 5.16 (m, 1H); 5.78 (s,1H); 7.32 (d, 2H); 7.93 (s, 1H).

(5R)-3-[4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(azidomethyl)oxazolidin-2-one

was prepared as described in WO 01/81350 A1 (intermediate for example86)

EXAMPLE 52(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-ethenyl-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(2-hydroxyethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 51) (142 mg, 0.31 mmol) was suspended in dry chloroform (15ml), thionylchloride (37 mg, 0.93 mmol) was added and the resultingmixture was refluxed for 12 hours. The solvent and eccess ofthionylchloride was removed under vacuum and the residue was dissolvedin acetonitrile (15 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (71 mg, 0.47mmol) was added and the resulting mixture was refluxed for 12 hours. Thesolvent was removed under vacuum and the residure was purified by flashchromatography on silica gel with 1.5% methanol in dichloromethane togive the title product (100 mg).

MS (ESP): 437.26 (MH⁺) for C₁₉H₁₈F₂N₄O₄S ¹H-NMR(DMSO-d₆) δ: 2.86 (m,2H); 3.37 (m, 2H); 3.92 (m, 1H); 3.93 (m, 2H); 4.25 (dd, 1H); 4.81 (d,2H); 5.18 (m, 1H); 5.31 (d, 1H); 5.78 (m, 1H); 0.86 (d, 1H); 6.72 (m,1H); 7.32 (d, 2H); 8.28 (s, 1H).

EXAMPLE 53(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-methoxymethyl-1,2,3-triazol-1-ylmethyl]-1,3-oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(azidomethyl)-1,3-oxazolidin-2-one(WO 01/81350 A1) (0.50 g, 1.3 mmol), and propargyl methyl ether (1 ml,11.9 mmol) were combined in toluene (4 ml). The mixture was stirred at100° C. for 16 hours to give a mixture of two regioisomeric products:tlc Rf's=0.45 and 0.25 respectively (silica gel, 40% acetonitrile indichloromethane). The mixture was resolved by flash columnchromatography on silica gel with gradient 10% to 50% acetonitrile indichloromethane. The lower migrating material (Rf=0.25) obtained afterchromatography was precipitated from dichloromethane solution with etherto give 0.26 g (44%) of the title compound as a white powder. Thestructure was confirmed by NOE experiments.

MS (ESP): 455.0 (MH⁺) for C₁₉H₂₀F₂N₄O₅S ¹H-NMR(DMSO-d₆) δ: 2.86 (m, 2H);3.25 (s, 3H); 3.37 (t, 2H); 3.92 (m, 3H); 4.26 (dd, 1H); 4.46 (s, 2H);4.83 (d, 2H); 5.19 (m, 1H); 5.77 (m, 1H); 7.32 (d, 2H); 8.16 (s, 1H).

EXAMPLE 54(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[(4-chloromethyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-azidomethyloxazolidin-2-one(WO 01/81350 A1) (500 mg, 1.3 mmol) and propargyl chloride (1.5 g, 20mmol) were added to toluene (1 ml) and heated in a Personal ChemistryMicrowave Reactor at 125° C. for 25 minutes. EtOAc (20 ml) was thenadded and the organic layer was washed with water (2×10 ml) and brine(2×10 ml), dried over sodium sulfate and then concentrated in vacuo.Chromatography on silica gel with 0–5% methanol in dichloromethane gavethe title compound (72 mg).

MS (ESP): 459.16 (MH⁺) for C₁₈H₁₇ClF₂N₄O₄S ¹H-NMR(DMSO-d₆) δ: 2.85 (m,2H); 3.6 (m, 2H); 3.91 (m, 3H); 4.26 (t, 1H); 4.84 (m, 4H); 5.18 (m,1H); 5.77 (s, 1H); 7.32 (d, 2H); 8.27 (s, 1H).

EXAMPLE 55(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-ethynyl-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-azidomethyloxazolidin-2-one(WO 01/81350 A1) (500 mg, 1.29 mmol) was added to 1,4-dichloro-2-butyne(2 ml) followed by addition of sodium hydroxide (310 mg, 7.74 mmol). Thereaction was heated in a Personal Chemistry Microwave Reactor at 125° C.for 25 minutes and then concentrated in vacuo. The residue was purfiriedby reverse phase HPLC eluting with 20–95% acetonitrile/water in 30mintues to give the title compound (10.5 mg).

MS (ESP): 435.20 (MH⁺) for C₁₉H₁₆F₂N₄O₄S ¹H-NMR(DMSO-d₆) δ: 2.86 (s,2H); 3.36 (m, 2H); 3.69 (m, 3H); 4.26 (s, 1H); 4.46 (s, 1H); 4.85 (m,2H); 5.2 (m, 1H); 5.78 (s, 1H); 7.32 (d, 2H); 8.54 (s, 1H).

EXAMPLE 56(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(1,1-dimethylethoxy)carbonylaminomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-azidomethyloxazolidin-2-one(WO 01/81350 A1) (500 mg, 1.3 mmol) and prop-2-ynyl-carbamic acidtert-butyl ester (1.5 g, 9.7 mmol) were reacted as described for Example54. Chromatography on silica gel with 0–5% methanol in dichloromethanegave the title product (67.5 mg).

MS (APCI): 539.0 (MH⁻) for C₂₃H₂₇F₂N₅O₆S ¹H-NMR(DMSO-d₆) δ: 1.4 (m, 9H);2.86 (s, 2H); 3.34 (m, 3H); 3.89 (m, 1H); 3.89 (m, 1H); 3.95 (s, 2H);4.17 (s, 2H); 4.24 (t, 1H); 4.81 (m, 2H); 5.16 (m, 1H); 5.77 (s, 1H);7.34 (d, 3H); 7.94 (s, 1H).

EXAMPLE 57(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(2-chloroethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(2-hydroxyethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one(Example 51) (300 mg, 0.66 mmol) was reacted with thionylchloride (78.5mg, 1.98 mmol) as described for Example 52. Chromatography on silica gelwith 2.5% methanol in dichloromethane gave the title compound (285 mg).

MS (ESP): 473.07 (MH⁺) for C₁₉H₁₉ClF₂N₄O₄S ¹H-NMR(CDCl) δ: 3.04 (m, 2H);3.21 (t, 2H); 3.25 (m, 2H); 3.79 (m, 2H); 3.85 (m, 2H); 3.96 (m, 1H);4.16 (dd, 1H); 4.77 (d, 2H); 5.33 (m, 1H); 5.77 (m, 1H); 7.09 (d, 2H);7.67 (s, 1H).

EXAMPLE 58(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[(4-nitro)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-azidomethyloxazolidin-2-one(WO 01/81350 A1) (200 mg, 0.44 mmol) and 1-dimethylamino-2-nitroethene(153 mg, 1.32 mmol) were mixed in dry 1,4-dioxane (0.5 ml) in amicrowave reaction tube. The resulting mixture was microwaved for 30minutes at 150° C. The solvent was removed under vacuum and the residuewas purified by flash chromatography on silica gel with with 1.25% ofmethanol in dichloromethane to give the title product (50 mg).

MS (ESP): 911.15 (2MH⁺) for C₁₇H₁₅F₂N₅O₆S ¹H-NMR(DMSO-d₆) δ: 2.86 (m,2H); 3.37 (m, 2H); 3.96 (m, 2H); 3.97 (m, 1H); 4.25 (dd, 1H); 4.96 (d,2H); 5.26 (m, 1H); 5.78 (m, 1H); 7.37 (d, 2H); 9.40 (s, 1H).

EXAMPLE 59(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[5-thiomethyl-2H-tetrazol-2-ylmethyl]oxazolidin-2-one

(5R)-3-[4-(3,6-Dihydro-1,1-dioxo-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)-2-oxazolidinone(WO 01/81350 A1) (500 mg, 1.39 mmol), 5-(thiomethyl)-1H-tetrazole (178mg, 1.53 mmol), diisopropylazodicarboxylate (309 mg, 1.53 mmol) andpolystyrene-triphenylphosphine (1.73 mmol/g loading: ArgonautTechnologies, Inc. Foster City, Calif. USA, 1.02 g, 1.73 mmol) weremixed in dichloromethane (10 ml). It was stirred at room temperature for12 hours, filtered and washed with aqueous NH₄Cl solution and brine. Thesolvent was removed under vacuum and the crude product was purified byflash chromatography on silica gel with 2% methanol in dichloromethaneto give 232 mg of the title compound.

MS (ESP): 458.14 (MH⁺) for C₁₇H₁₇F₂N₅O₄S₂ ¹H-NMR(DMSO-d₆) δ: 2.62 (s,3H); 2.86 (m, 2H); 3.37 (m, 2H); 3.91 (m, 1H); 3.95 (m, 2H); 4.29 (dd,1H); 5.18 (m, 2H); 5.31 (m,1H); 5.78 (s, 1H); 7.31 (d, 2H).

The intermediate for this compound was prepared as follows:

(5R)-3-[4-(3,6-Dihydro-1,1-dioxido-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)-2-oxazolidinone

This compound was prepared according to WO 01/81350 A1, page 96.

EXAMPLE 60(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[5-(methylcyano)tetrazol-2-ylmethyl]oxazolidin-2-one

Malonitrile (11 g, 0.167 mol), sodium azide (10.8 g, 0.166 mol), andammonium chloride (8.92 g, 0.167 mol) were suspended in DMF (50 ml) andheated at 80° C. for 16 hours. The mixture was poured into water,acidified with concentrated HCl, and extracted twice withdichloromethane. The combined organic phases were dried over sodiumsulfate and evaporated to give an oily brown residue, which yieldedcrystals upon drying in vacuo. The crystals were collected and rinsedwith dichloromethane to afford 1H-tetrazol-5-ylacetonitrile (CAS#13616-36-9) as a light brown crystalline solid (2.92 g, 16%).

1H-tetrazol-5-ylacetonitrile (0.27 g, 2.48 mmol),(5R)-3-[4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one(WO 01/81350 A1) (0.50 g, 1.39 mmol), and triphenylphosphine (0.55 g,2.1 mmol) were combined in dry tetrahydrofuran (5 ml), and cooled on anice-water bath. Diisopropylazodicarboxylate (0.41 ml, 2.58 mmol) wasadded dropwise over several minutes and the mixture was allowed to warmslowly to room temperature with stirring over 16 hours. Methanol (3 ml)was added, followed by evaporation and purification by chromatography onsilica gel with 10% to 15% acetonitrile in dichloromethane. The materialobtained after chromatography was precipitated from dichloromethanesolution with ether to remove residual triphenylphosphine oxide. Thisgave the title compound as a white powder (0.495 g, 79%).

MS (ESP): 451.0 (MH⁺) for C₁₈H₁₆F₂N₆O₄S ¹H-NMR(DMSO-d₆) δ: 2.86 (m, 2H);3.36 (m, 2H); 3.93 (m, 3H); 4.31 (t, 1H); 4.55 (s, 2H); 5.17 (dd, 1H);5.26 (m, 1H); 5.32 (m, 1H); 5.77 (m, 1H); 7.33 (dm, 2H).

EXAMPLE 61 (5R)3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[5-cyclopropyl-2H-tetrazol-2-ylmethyl]oxazolidin-2-one

Cyclopropylcarbonitrile (2 ml, 27 mmol) was added to a solution oftrimethylsilylazide (4.3 ml, 32.5 mmol) and trimethylaluminum (16 ml ofa 2M toluene solution, 32 mmol) at 0° C. The cold bath was removed, themixture was stirred at room temperature for 15 minutes, then warmed to80° C. for 16 hours. The solution was carefully added to a slurry of iceand 1N HCl, followed by acidification with concentrated HCl andextraction twice with ethyl acetate. The combined organic phases werewashed with saturated NaCl, dried over sodium sulfate, and evaporated toyield a solid residue. Trituration with 1:1 hexane:ethyl acetate gave5-cyclopropyl-1H-tetrazole (CAS# 27943–07–3) as a white crystallinesolid (1.5 g, 51%). 5-cyclopropyl-1H-tetrazole (0.183 g, 1.66 mmol),(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one(WO 01/81350 A1) (0.30 g, 0.84 mmol), polystyrene-triphenylphosphine(1.73 mmol/g loading: Argonaut Technologies, Inc. Foster City, Calif.USA, 1.46 g, 2.53 mmol) and diisopropylazodicarboxylate (0.33 ml, 1.68mmol) were reacted as described for Example 58. Purification was carriedout by chromatography on silica gel with 10% acetonitrile indichloromethane. The material obtained after chromatography wasprecipitated from dichloromethane solution with ether to yield the titlecompound as a white powder (0.28 g, 74%).

MS (ESP): 452.0 (MH⁺) for C₁₉H₁₉F₂N₅O₄S ¹H-NMR(DMSO-d₆) δ: 0.83 (m, 2H);1.05 (m, 2H); 2.18 (m, 1H); 2.87 (bm, 2H); 3.37 (m, 2H); 3.90 (dd, 1H);3.95 (bs, 2H); 4.28 (t, 1H); 5.04 (dd, 1H); 5.10 (dd, 1H); 5.28 (m, 1H);5.77 (t, 1H); 7.29 (d, 2H).

1. A compound of the formula (I), or a pharmaceutically-acceptable salt,or an in-vivo-hydrolysable ester thereof,

wherein —N-HET is selected from the structures (Id) or (Ie) below:

wherein; R1 is selected from a substituent from the group (R1a) whereinR1 is halogen, hydroxy, (1–4C)alkoxy, (2–4C)alkenyloxy, (2–4C)alkenyl,(2–4C)alkynyl (optionally substituted on the terminal carbon by CH₂═CH—,AR2, AR2a or AR2b, wherein AR2, AR2a and AR2b are defined hereinbelow),(3–6C)cycloalkyl, (3–6C)cycloalkenyl, (1–4C)alkyl-S(O)q-(wherein q is 0,1 or 2); or R1 is selected from the group (R1b) wherein R1 is a(1–4C)alkyl group which is substituted by one substituent selected fromhydroxy, halo, (1–4C)alkoxy, (2–4C)alkenyloxy, (1–4C)alkyl-S(O)q-(wherein q is 0, 1 or 2), AR1-S(O)q- (wherein q is 0, 1 or 2 and AR1 isdefined hereinbelow), AR2-S(O)q- (wherein q is 0, 1 or 2), AR2a-S(O)q-(wherein q is 0, 1 or 2), benzyl-S(O)q- (wherein q is 0, 1 or 2),(3–6C)cycloalkyl, (3–6C)cycloalkenyl, (1–4C)alkyl-OCO—NH—; or R1 isselected from a group of formula (R1c1): (R1c1) a fully saturated4-membered monocyclic ring containing 1 or 2 heteroatoms independentlyselected from O and S (optionally oxidised), and linked via a ringnitrogen or carbon atom; or or R1 is selected from the group (R1d)formyl, (1–4C)alkylcarbonyl, (1–4C)alkoxycarbonyl; and wherein at eachoccurrence of an R1 substituent containing an alkyl, alkenyl, alkynyl,cycloalkyl or cycloalkenyl moiety in (R1a), (R1b) or (R1c1) each suchmoiety is optionally further substituted on an available carbon atomwith one, two, three or more substituents independently selected from F,Cl Br, and OH; Q is Q1;

wherein R² and R³ independently selected from H, F, Cl, CF₃, OMe, SMe,Me and Et; wherein B, is O or S; wherein T is (TC4):

wherein in (TC4): n1 is 1 or 2; o1 is 1 or 2 and n1+o1=2 or 3; >A₃-B₃-is >C═C(Rr)- and G is —S—, —SO—, —SO₂—; Rp is hydrogen (1–4C)alkyl(other than when such substitution is defined by >A₃-B₃), hydroxy,(1–4C)alkoxy or (1–4C)alkanoyloxy; Rr is (independently whereappropriate) hydrogen or (1–4C)alkyl; and, other than the ringsubstitution defined by G, >A₃-B₃-and Rp, each ring system may beoptionally further substituted on a carbon atom not adjacent to the linkat >A₃- by up to two substituents independently selected from(1–4C)alkyl, fluoro(1–4C)alkyl (including trifluoromethyl),(1–4C)alkyl-thio-(1–4C)alkyl, hydroxy-(1–4C)alkyl, amino,amino-(1–4C)alkyl, (1–4C)alkanoylamino, (1–4C)alkanoylamino-(1–4C)alkyl,carboxy, (1–4C)alkoxycarbonyl, ARc-oxymethyl, ARc-thiomethyl, oxo (═O)or independently selected from Rc (if such substituents are not alreadydefined herein in (TC)); and also hydroxy or halo (the last two optionalsubstituents only when G is —O— or —S—); wherein AR1 is an optionallysubstituted phenyl or optionally substituted naphthyl; AR2 is anoptionally substituted 5- or 6-membered, fully unsaturated (i.e with themaximum degree of unsaturation) monocyclic heteroaryl ring containing upto four heteroatoms independently selected from O, N and S (but notcontaining any O—O, O—S or S—S bonds), and linked via a ring carbonatom, or a ring nitrogen atom if the ring is not thereby quaternised;AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systemsretaining some, but not the full, degree of unsaturation), linked via aring carbon atom or linked via a ring nitrogen atom if the ring is notthereby quaternised.
 2. A compound of the formula (I) as claimed inclaim 1, or a pharmaceutically-acceptable salt or anin-vivo-hydrolysable ester thereof wherein R1 is selected from (a)hydrogen; (b) fluorine, chlorine, or bromine; (C) cyano; (d)fluoromethyl, chloromethyl, bromomethyl, cyanomethyl, azidomethyl,hydroxymethyl; (e) difluoramethyl; (f) trifluoromethyl; and (g) ethynylor substituted athynyl.
 3. A compound of claim 1 which is a compound ofthe formula (IB):

wherein —N-MET is 1,2,3-triazol-1-yl; R1 is selected from (R1a) and(R1b); R² and R³ are independently hydrogen or fluoro; and T is TC4. 4.A compound of claim 3, wherein —N-HET is 1,2,3-triazol-1-yl; R1 isselected from (R1a), (R1b) and (R1d); R² and R³ are independentlyhydrogen or fluoro; and T is TC4.
 5. A compound of the formula (I) asclaimed in claim 1, or a pharmaceutically-acceptable salt or an in-vivohydrolysable ester thereof, which is a compound selected from:(5R)-3-[4-(1(R,S)-oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-carbonitrile)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1(R,S)-oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-azidomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1(R,S)-oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-aminomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1(R,S)-oxo-3,6-dihydro-2H-thiopyran-4yl)-3-fluorophenyl]-5-[(4-(aminocarbonyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1(R,S)-oxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-(methoxycarbonyl)aminomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-{[4-[(aminomethaneiminiumbromide)thiomethyl]-1,2,3-triazol-1-yl}methyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(1H-1,2,3-triazol-4-ylthiomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(1H-imidazol-2-ylthio)methyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(dimethylamino)methyl-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2-(3-methyl-5-isoxazolyl)ethynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(2-(ethylmethylamino)-2-axoethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-(2-(dimethylamino)-2-oxoethyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(ethylaminocarbonyloxymethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-amino)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;(5R)-3-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl)-5-[(4-acetylamino)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one;5(R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl-5-[4-(4-dimethylamino-2-butynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;5(R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-(4-diethylamino-2-butynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;5(R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(4-(4-(2,5-dihydro-1H-pyrrol-1-y)-2-butynyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;5(R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(4-(4-(morpholinyl)-2-butynyl)-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one;(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[4-(1,1-dimethylethoxy)carbonylaminomethyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one;and(5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[(4-nitro)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one.6. A pro-drug of a compound as claimed in claim
 1. 7. A pharmaceuticalcomposition which comprises a compound of the invention as claimed inclaim 1, or a pharmaceutically-acceptable salt or an in-vivohydrolysable ester thereof and a pharmaceutically-acceptable diluent orcarrier.
 8. A process for the preparation of a compound of formula (I)as claimed in claim 1 or pharmaceutically acceptable salts or in-vivohydrolysable esters thereof, which process comprises one of processes(a) to (h); (a) by modifying a substituent in, or introducing a newsubstituent into, the substituent group R1 of HET of another compound offormula (I); (b) by reaction of a compound of formula (II):

wherein Y is a displaceable group with a compound of the formula (III):HET  (III) wherein HET (of formula (Ia) to (If), already substituted andoptionally protected) is HET-H free-base form or HET-anion formed fromthe free base form; or (c) by reaction of a compound of the formula(IV):Q-z  (IV) wherein Z is an isocyanate, a nine or urethane group with anepoxide of the formula (V); or with a related compound of formula (VI)where the hydroxy group at the internal C-atom is conventionallyprotected and where the leaving group Y at the terminal C-atom is aconventional leaving group; or

(d) (i) by coupling, using catalysis by transition metals such aspalladium(0), of a compound of formula (VII):

wherein Y′ is a group HET as hereinbefore defined, X is a replaceablesubstituent; with a compound of the formula (VIII), or an analoguethereof, which is suitable to give a T substituent as defined by(TA)-(TE), in which the link is via an sp² carbon atom (D=CH═C-Lg whereLg is a leaving group; or as in the case of reactions carried out underHeck reaction conditions Lg may also be hydrogen) or in which the linkis via an N atom (D=NH)

where T₁ and T₂ may be the same or different or may together with D forma ring of type T; (d) (II) by coupling, using catalysis by transitionmetals such as palladium(0), of a compound of formula (VIIA):

wherein Y′ is a group HET as hereinbefore defined, with a compound[Aryl]-X, where X is a replaceable substituent; (e) Where N-HET is1,2,3-triazole by cycloaddition via the azide (wherein Y in (II) isazide), with a substituted acetylene or a masked acetylene; (f) WhereN-HET is 1,2,3-triazole by reaction of a compound of formula (II) whereY=NH₂ (primary amine) with a compound of formula (IX), namely thearenesulfonylhydrazone of a methyl ketone that is further geminallysubstituted on the methyl group by two substituents (Y′ and Y′ ) capableof being eliminated from this initial, and the intermediate, substitutedhydrazones as HY′ and HY″ (or as conjugate bases thereof);

(g) where N-HET is 1,2,3-triazole regioselective synthesis may becarried out by cycloaddition via the azide (wherein Y in (II) is azide)with a terminal alkyne using Cu(I) catalysis to give 4-substituted1,2,3-triazoles;

(h) where N-HET is 1,2,3-triazole regioselective synthesis may becarried out by cycloaddition via the azide (wherein Y in (II) is azide)with an alpha-halovinylsulfonylchloride (XIII); and thereafter ifnecessary: (I) removing any protecting groups; (ii) forming apharmaceutically-acceptable salt; (iii) forming an in-vivo hydrolysableester.